{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:26:50Z","timestamp":1790803610067,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Leptomeningeal metastasis (LM) is a severe complication of advanced non-small-cell lung cancer (NSCLC) that is increasingly detected due to improved diagnostics. Intrathecal therapy, which involves delivering drugs directly into the subarachnoid space, has become a key treatment approach. A variety of cytotoxic drugs, targeted therapies, immune-checkpoint inhibitors, and combination treatments are now available through different intrathecal protocols, offering new hope to patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Extensive searches were conducted in PubMed, Embase, the Cochrane Library, Web of Science, Wanfang Data, CNKI, and VIP. Data collected included histological subtype, intrathecal delivery method, treatment regimen, median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) in \u226510% of patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twelve clinical studies with 544 patients (average age 53.27 years) met the criteria. Drug delivery was via lumbar puncture or Ommaya reservoir. Objective response rates were 34.5%\u201386.4%, and disease control rates were 62.5%\u201394.9%. Three trials reported progression-free survival of 3.5, 6.3, and 9.6 months, with overall survival from 3.66 to 17 months. AEs in over 10% of patients included myelosuppression, gastrointestinal issues, and neurological symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Intrathecal therapy offers significant clinical benefits, especially when combined with other treatments, with a manageable toxicity profile.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1788293","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:31:14Z","timestamp":1782365474000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Intrathecal chemotherapy for leptomeningeal metastasis of non-small-cell lung cancer: a systematic review"],"prefix":"10.3389","volume":"17","author":[{"given":"Dan","family":"Wang","sequence":"first","affiliation":[{"name":"Clinical Medical College, Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]},{"name":"Department of Pharmacy, The First Affliated Hospital of Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]},{"name":"Department of Oncology, The First Affliated Hospital of Chengdu Medical College","place":["Chengdu, China"]},{"name":"Department of Oncology, The First Affiliated Hospital of Traditional Chinese Medical of Chengdu Medical College-Xindu Hospital of Traditional Chinese Medical","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Zheng","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]},{"name":"Department of Pharmacy, The First Affliated Hospital of Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]},{"name":"Department of Pharmacy, The First Affliated Hospital of Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]},{"name":"Department of Pharmacy, The First Affliated Hospital of Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]},{"name":"Department of Pharmacy, The First Affliated Hospital of Chengdu Medical College","place":["Chengdu City, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.cell.2017.02.025","article-title":"Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis","volume":"168","author":"Boire","year":"2017","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1038\/s41591-020-0918-0","article-title":"Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis","volume":"26","author":"Brastianos","year":"2020","journal-title":"Nat. Medicine"},{"key":"B3","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/s0169-5002(02)00504-4","article-title":"Intrathecal gemcitabine chemotherapy for non-small cell lung cancer patients with meningeal Carcinomatosis\u2014A case report","volume":"40","author":"Chen","year":"2003","journal-title":"Lung Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"844","DOI":"10.3390\/cancers15030844","article-title":"Advances in the management of central nervous system metastases in non-small cell lung cancer","volume":"15","author":"D\u2019Aiello","year":"2023","journal-title":"Cancers"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1016\/j.jtho.2021.04.018","article-title":"Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating tyrosine kinase inhibitor-failed leptomeningeal metastases from EGFR-mutant NSCLC\u2014A prospective, open-label, single-arm phase 1\/2 clinical trial (unique identifier: chiCTR1800016615)","volume":"16","author":"Fan","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"102384","DOI":"10.1016\/j.esmoop.2024.102384","article-title":"Efficacy and safety of intrathecal pemetrexed for TKI-Failed leptomeningeal metastases from EGFR+ NSCLC: an expanded, single-arm, phase II clinical trial","volume":"9","author":"Fan","year":"2024","journal-title":"ESMO Open"},{"key":"B7","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.lungcan.2017.02.022","article-title":"Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small cell lung cancer patient","volume":"108","author":"Gion","year":"2017","journal-title":"Lung Cancer Amsterdam, Neth."},{"key":"B8","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/s41591-022-02170-x","article-title":"Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results","volume":"29","author":"Glitza Oliva","year":"2023","journal-title":"Nat. Medicine"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e24724","DOI":"10.1097\/md.0000000000024724","article-title":"Risk factors for brain metastases from non-small-cell lung cancer: a protocol for observational study","volume":"100","author":"He","year":"2021","journal-title":"Med. Baltim."},{"key":"B10","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s11060-023-04412-5","article-title":"First in-human intrathecal delivery of bevacizumab for leptomeningeal spread from recurrent glioblastoma: rationale for a dose escalation trial","volume":"164","author":"Holdaway","year":"2023","journal-title":"J. Neuro-Oncology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/s11060-023-04483-4","article-title":"Effects of intrathecal pemetrexed on the survival of patients with leptomeningeal metastasis from lung adenocarcinoma: a propensity score matching analysis","volume":"165","author":"Hong","year":"2023","journal-title":"J. Neuro-Oncology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"12","DOI":"10.6004\/jnccn.2023.0002","article-title":"NCCN guidelines\u00ae insights: central nervous system cancers, version 3.2024","volume":"21","author":"Horbinski","year":"2024","journal-title":"J. Natl. Compr. Cancer Netw. JNCCN"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.1093\/jjco\/hyab155","article-title":"Clinical efficacy and safety of different doses of intrathecal methotrexate in the treatment of leptomeningeal carcinomatosis: a prospective and single-arm study","volume":"51","author":"Hou","year":"2021","journal-title":"Jpn. Journal Clinical Oncology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"658","DOI":"10.4103\/jcrt.jcrt_2071_23","article-title":"Outcomes, responses, and prognostic analyses of intrathecal combined treatment for leptomeningeal metastasis from lung adenocarcinoma","volume":"20","author":"Huang","year":"2024","journal-title":"J. Cancer Research Therapeutics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"126","DOI":"10.4103\/0973-1482.191638","article-title":"Prolonged overall survival of patients with leptomeningeal carcinomatosis from nonsmall cell lung cancer","volume":"12","author":"Jiao","year":"2016","journal-title":"J. Cancer Research Therapeutics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"695","DOI":"10.19401\/j.cnki.1007-3639.2024.07.009","article-title":"Clinical research progress of intrathecal therapy in the treatment of leptomeningeal metastasis","volume":"34","author":"Kang Xun","year":"2024","journal-title":"CHINA Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"75","DOI":"10.4103\/0971-5851.133726","article-title":"Carcinomatous meningitis in non-small cell lung cancer: palliation with intrathecal treatment","volume":"35","author":"Kumar","year":"2021","journal-title":"Indian J. Med. Paediatr. Oncol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"101624","DOI":"10.1016\/j.esmoop.2023.101624","article-title":"Leptomeningeal metastasis from solid tumours: EANO\u2013ESMO clinical practice guideline for diagnosis, treatment and follow-up","volume":"8","author":"Le Rhun","year":"2023","journal-title":"ESMO Open"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2341","DOI":"10.21037\/apm-19-521","article-title":"Treatment response to intrathecal chemotherapy with pemetrexed via an ommaya reservoir in EGFR-Mutated leptomeningeal metastases from non-small cell lung cancer: a case report","volume":"9","author":"Li","year":"2020","journal-title":"Ann. Palliative Medicine"},{"key":"B20","doi-asserted-by":"publisher","first-page":"22372","DOI":"10.1038\/s41598-022-26131-z","article-title":"Brain parenchymal and leptomeningeal metastasis in non-small cell lung cancer","volume":"12","author":"Li","year":"2022","journal-title":"Sci. Reports"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e94","DOI":"10.1016\/j.cllc.2022.11.011","article-title":"Safety, pharmacokinetic and clinical activity of intrathecal chemotherapy with pemetrexed via the ommaya reservoir for leptomeningeal metastases from lung adenocarcinoma: a prospective phase I study","volume":"24","author":"Li","year":"2023","journal-title":"Clin. Lung Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"71","DOI":"10.19401\/j.cnki.1007-3639.2019.01.011","article-title":"Shanghai expert consensus on the management of brain metastasis of non-small cell lung cancer with driver gene mutations","volume":"29","author":"Liang Xh","year":"2019","journal-title":"CHINA Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3779\/j.issn.1009-3419.2025.102.39","article-title":"Chinese expert consensus on clinical management of oncogene addicted non-small cell lung cancer with leptomeningeal metastasis (2026 edition)","volume":"29","year":"2026","journal-title":"Chin. J. Lung Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"4233","DOI":"10.21037\/apm-20-2086","article-title":"Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis","volume":"9","author":"Miao","year":"2020","journal-title":"Ann. Palliative Medicine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cllc.2024.04.005","article-title":"Clinical outcomes of patients with non-small cell lung cancer leptomeningeal disease following receipt of EGFR-targeted therapy, immune-checkpoint blockade, intrathecal chemotherapy, or radiation therapy alone","volume":"25","author":"Mills","year":"2024","journal-title":"Clin. Lung Cancer"},{"key":"B26","article-title":"NCCN guidelines version 3.2025 central nervous system cancers","author":"Nabors","year":"2025","journal-title":"NCCN"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e1869","DOI":"10.1634\/theoncologist.2020-0640","article-title":"Erlotinib for non-small cell lung cancer with leptomeningeal metastases: a phase II study (LOGIK1101)","volume":"25","author":"Nosaki","year":"2020","journal-title":"Oncologist"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e57322","DOI":"10.7759\/cureus.57322","article-title":"Intrathecal trastuzumab for HER2-Positive cancer of unknown primary leptomeningeal metastasis: a case report","volume":"16","author":"Oka","year":"2024","journal-title":"Cureus"},{"key":"B29","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1158\/1078-0432.ccr-22-1585","article-title":"Leptomeningeal metastasis from non\u2013small cell lung cancer and current landscape of treatments","volume":"29","author":"Ozcan","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"109740","DOI":"10.1016\/j.radonc.2023.109740","article-title":"A phase II study of concurrent involved-field radiotherapy and intrathecal chemotherapy for leptomeningeal metastasis from solid tumors","volume":"186","author":"Pan","year":"2023","journal-title":"Radiotherapy Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"224","DOI":"10.12659\/AJCR.894061","article-title":"Prolonged response of meningeal carcinomatosis from non-small cell lung cancer to salvage intrathecal etoposide subsequent to failure of first-line methotrexate: a case report and literature review","volume":"16","author":"Park","year":"2015","journal-title":"Am. J. Case Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s11060-014-1486-2","article-title":"Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study","volume":"119","author":"Scott","year":"2014","journal-title":"J. Neuro-Oncology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s00280-010-1522-7","article-title":"Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats","volume":"68","author":"Sun","year":"2010","journal-title":"Cancer Chemotherapy Pharmacology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/cncr.30911","article-title":"Leptomeningeal metastasis from systemic cancer: review and update on management","volume":"124","author":"Wang","year":"2017","journal-title":"Cancer"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.3390\/cells10102620","article-title":"Research progress and challenges in the treatment of central nervous system metastasis of non-small cell lung cancer","volume":"10","author":"Wang","year":"2021","journal-title":"Cells"},{"key":"B36","doi-asserted-by":"publisher","first-page":"S650","DOI":"10.1016\/j.jtho.2023.09.1239","article-title":"EP12.01-24 high-dose aumolertinib combined intrathecal chemotherapy for LM from EGFR-mutated NSCLC with meningeal symptoms as the first symptom","volume":"18","author":"WangW","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.3892\/ol.2016.4783","article-title":"Intrathecal chemotherapy as a treatment for leptomeningeal metastasis of non-small cell lung cancer: a pooled analysis","volume":"12","author":"Wu","year":"2016","journal-title":"Oncol. Letters"},{"key":"B38","doi-asserted-by":"publisher","first-page":"914","DOI":"10.3779\/j.issn.1009-3419.2016.05.08","article-title":"Analysis of the efficacy of intrathecal methotrexate for leptomeningeal metastases from lung cancer","volume":"17","author":"Wu Xi","year":"2019","journal-title":"Oncol. Prog."},{"key":"B39","doi-asserted-by":"publisher","first-page":"11795549231205206","DOI":"10.1177\/11795549231205206","article-title":"The riddle of the sphinx: progress in leptomeningeal metastasis of non\u2013small cell lung cancer","volume":"17","author":"Zhao","year":"2023","journal-title":"Clin. Med. Insights Oncol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e795","DOI":"10.1097\/CAD.0000000000001222","article-title":"Complete remission in leptomeningeal metastasis of NSCLC with rare EGFR-SEPT14 fusion treated with osimertinib combined with intrathecal chemotherapy with pemetrexed","volume":"33","author":"Zheng","year":"2021","journal-title":"Anti-cancer Drugs"},{"key":"B41","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.annonc.2025.09.140","article-title":"The evolving landscape of leptomeningeal metastases from NSCLC: an international, contemporary, multicenter cohort study","volume":"37","author":"Zheng","year":"2026","journal-title":"Ann. Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1377451","DOI":"10.3389\/fonc.2024.1377451","article-title":"Double-dose osimertinib combined with intrathecal injection of pemetrexed improves the efficacy of EGFR-Mutant non-small cell lung cancer and leptomeningeal metastasis: case report and literature review","volume":"14","author":"Zhong","year":"2024","journal-title":"Front. Oncology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1186\/s12885-023-10806-5","article-title":"Intrathecal chemotherapy combined with systemic therapy in patients with refractory leptomeningeal metastasis of non-small cell lung cancer: a retrospective study","volume":"23","author":"Zhou","year":"2023","journal-title":"BMC Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3760\/cma.j.cn112152-20200711-00647","article-title":"Clinical trials on intrathecal pemetrexed treated leptomeningeal metastases from solid tumors","volume":"44","author":"Zy Pan","year":"2022","journal-title":"Clin. J. Oncol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1788293\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:31:19Z","timestamp":1782365479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1788293\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":44,"alternative-id":["10.3389\/fphar.2026.1788293"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1788293","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]},"article-number":"1788293"}}