Systematic review of intrathecal therapy for leptomeningeal metastasis in non-small cell lung cancer

Leptomeningeal metastasis (LM) from non–small cell lung cancer (NSCLC) is a devastating complication associated with a poor prognosis, with historical median overall survival (OS) of approximately 3–6 months. Limited penetration of systemic therapies across the blood–brain and blood–cerebrospinal fluid (CSF) barriers has prompted increasing interest in intrathecal (IT) drug delivery. The Ommaya reservoir, an implantable ventricular access device, provides a practical route for achieving therapeutic drug concentrations within the CSF and has been increasingly applied in NSCLC-related LM. To systematically review contemporary evidence regarding the efficacy, safety, and delivery-route considerations of intrathecal (IT) therapy in NSCLC-related LM, with particular emphasis on the clinical role of Ommaya reservoir–based delivery. A comprehensive literature search of PubMed, MEDLINE, Embase, Scopus, Web of Science, the Cochrane Library, and CNKI was conducted from database inception to September 30, 2025. Original studies reporting clinical outcomes of intrathecal chemotherapy and/or targeted therapy in adult patients with NSCLC-related LM were reviewed in accordance with PRISMA 2020 guidelines. Delivery route (Ommaya reservoir vs lumbar puncture) was extracted when reported. Studies without extractable NSCLC-LM–specific clinical outcome data and narrative reviews/guidelines were excluded from the primary clinical efficacy synthesis and used for contextual background only. Ten original studies met predefined criteria for NSCLC-specific clinical efficacy synthesis. Across these studies, intrathecal therapy was associated with neurological improvement and CSF cytology clearance in a substantial proportion of patients. Traditional IT agents such as methotrexate or cytarabine were generally associated with modest survival outcomes, whereas more recent studies evaluating IT pemetrexed and molecularly guided regimens reported longer survival in selected cohorts, particularly in EGFR-mutant NSCLC-LM. Studies using Ommaya reservoir–based delivery highlighted practical advantages in repeated CSF access and treatment continuity, while device-related complications (e.g., infection and catheter malfunction) were generally manageable. However, most available evidence derives from retrospective, single-center cohorts with heterogeneous treatment protocols, and randomized comparative evidence remains limited. Intrathecal therapy represents an important component of multimodal management for selected patients with NSCLC-related LM. Ommaya reservoir–based delivery may offer practical advantages for repeated treatment and CSF monitoring in appropriately selected patients, with acceptable toxicity and manageable device-related risks. Emerging data on pemetrexed-based intrathecal regimens and other molecularly informed approaches suggest potential benefit in selected subgroups, but prospective, multicenter, mutation-stratified studies are needed to refine patient selection, optimize dosing strategies, and define the comparative role of different intrathecal delivery routes.