Efficacy and safety of intrathecal chemotherapy in leptomeningeal disease: a global retrospective multicenter analysis and review of the literature

Background Leptomeningeal disease (LMD) is a devastating complication of cancer with limited therapeutic options and poor prognosis. It affects approximately 5–15% of patients with solid or hematopoietic malignancies. The optimal route of chemotherapy delivery for LMD patients remains controversial, with intrathecal administration theoretically offering direct access to the central nervous system. The effectiveness and safety of intrathecal chemotherapy (ITC) remain contentious, and most previous studies have been limited to small sample sizes. We aimed to assess the efficacy and safety of ITC in LMD patients using global data. Methods This was a retrospective cohort study using electronic health record data from the International Collaborative TriNetX Network, comparing outcomes among patients with LMD across cancer types who received ITC plus systemic chemotherapy versus systemic chemotherapy alone. The study included all cancer types across 106 healthcare organizations, encompassing more than 156 million patients. The analysis was conducted on August 12, 2025, and eligible index events were restricted by the TriNetX platform to the preceding 20 years (August 12, 2005, through August 12, 2025). After including all cancer patients with LMD of both sexes aged between 18 and 90 years, we first excluded patients who received radiotherapy to the central nervous system. Second, 2311 subjects who received systemic chemotherapy alone and 292 subjects who received ITC plus systemic chemotherapy were included and compared using multivariate Cox regression to calculate hazard ratios (HRs). Third, propensity score matching (PSM) was performed using age, sex, primary cancer type, treatment interventions, and baseline laboratory values at diagnosis. This yielded 247 cases in each cohort, which were compared using univariate survival analysis with HRs. The primary outcome of both the univariate and multivariate analyses was all-cause mortality at multiple time points. Secondary outcomes included chemotherapy-related adverse effects, meningitis, hydrocephalus, cognitive-communication deficits, seizures, sepsis, and hypotension following treatment. A subanalysis was also performed to assess the isolated efficacy and safety of specific ITCs (in combination with systemic chemotherapy), such as methotrexate and cytarabine, compared with systemic chemotherapy alone. Finally, we conducted a literature review from inception through December 2025 to identify all prospective phase 2 and 3 clinical trials that evaluated the efficacy and safety of ITC in patients with LMD. Findings We found that the predominant cases receiving ITC were of hematopoietic and lymphoid origin (176 patients; 71.3% in ITC vs. 173; 70% in controls), followed by breast, lung, and melanoma primary cancers (48 [19.4%], 21 [8.5%], and 17 [6.9%] in ITC vs. 59 [23.9%], 20 [8.1%], and 14 [5.7%], respectively). Multivariate Cox regression analysis revealed a significant reduction in 30-day mortality associated with ITC (HR 0.45, 95% CI 0.26–0.76; p=0.003). At 90 days, the association with mortality did not reach statistical significance (HR = 0.75; 95% CI, 0.55–1.02; p=0.066). By 180 days, mortality rates did not differ between cohorts (HR = 0.93; 95% CI, 0.73–1.20; p=0.58). One-year univariate survival analysis post-PSM indicated worse survival with ITC (HR = 1.34; 95% CI, 1.01–1.78; p=0.04). Over the follow-up period, patients receiving ITC experienced higher rates of adverse events, including meningitis (36.8% vs. 21.5%; HR 1.94; p < 0.001), hydrocephalus at 30 days (8.5% vs. 4.0%; HR 3.04; p=0.01), and cognitive communication deficits (26.3% vs. 16.2%; HR 1.75; p=0.01). Interpretation This large-scale study provides important insights into the role of ITC in both solid and hematologic malignancies. Although the overall findings did not demonstrate a long-term survival benefit, ITC was associated with improved 30-day survival (HR = 0.4; p < 0.05). No difference was observed at 90 days, and beyond that time, an inverse effect emerged, possibly reflecting treatment-related toxicities and cancer-related complications. Given that survival in LMD typically ranges from 4 to 16 weeks and rarely exceeds 6 months, these results suggest that ITC provides a short-term survival advantage but may not alter, or may worsen, longer-term outcomes with a significant increase in chemotherapy adverse events, hydrocephalus, meningitis, and communicative cognitive impairment. Funding None.