The Comparative Study of Ommaya Reservoir versus Lumbar Puncture for Intrathecal Chemotherapy in Patients with Leptomeningeal Metastasis Disease

The Comparative Study of Ommaya Reservoir versus Lumbar Puncture for Intrathecal Chemotherapy in Patients with Leptomeningeal Metastasis Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Comparative Study of Ommaya Reservoir versus Lumbar Puncture for Intrathecal Chemotherapy in Patients with Leptomeningeal Metastasis Disease Lushao Zhang, Mingtao Feng, Yuechao Yang, Zhe Qi, Bihani Pokharel, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9469387/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 14 You are reading this latest preprint version Abstract Background Leptomeningeal metastasis (LM) is a lethal complication of advanced malignancy with limited therapeutic options and poor survival. Intrathecal chemotherapy represents a standard treatment for LM and can be administered via repeated lumbar puncture (LP) or an intraventricular Ommaya reservoir. However, the comparative efficacy and safety of these two administration routes remain unclear. This study aimed to compare clinical outcomes of intrathecal chemotherapy delivered by Ommaya reservoir versus LP in patients with LM, and to provide further evidence for clarifying the advantages of Ommaya reservoir in clinical practice. Methods We systematically searched MEDLINE, PubMed, and Web of Science for relevant studies published between 1986 and 2026. Studies directly comparing intrathecal chemotherapy delivered via Ommaya reservoir and LP were included in the meta-analysis. Disease control rate (DCR) was pooled as odds ratios (OR) using the Mantel–Haenszel method, and overall survival (OS) was pooled as hazard ratios (HR) using the inverse-variance method. Because adverse events (AEs) were incompletely reported in comparative studies, an additional safety analysis including single-arm cohorts was conducted using a binomial generalized linear mixed model (GLMM) with a logit link. Results A total of four comparative studies were enrolled in our meta-analysis. Three studies contributed data on DCR, and three studies contributed data on OS. The pooled analysis showed no significant difference in DCR between the Ommaya and LP groups (OR 1.43; 95% CI 0.76–2.68, p = 0.27), with moderate heterogeneity (I² = 66%). In contrast, Ommaya-based intraventricular delivery was associated with significantly improved OS compared with LP (HR 0.39; 95% CI, 0.25–0.61, p < 0.0001), with no significant heterogeneity (I² = 0%). In the additional safety analysis of six single-arm cohorts, Ommaya delivery was associated with lower estimated risks of overall AEs than LP(OR 0.43; 95% CI, 0.21–0.87, p = 0.0191). Conclusion Ommaya reservoir–based intraventricular administration of intrathecal chemotherapy may provide a survival advantage and lower risk of AEs over LP in patients with LM. leptomeningeal metastasis intrathecal chemotherapy Ommaya reservoir lumbar puncture overall survival meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Leptomeningeal metastasis(LM) is an lethal complication of advanced cancer, defined by the spread of maligant cells to the leptomeninges and cerebrospinal fluid (CSF). LM occurs in patients with metastatic solid tumors or hematologic cancers , especically in those with the breast, lung, or melanoma [1-2].The diagnosis of LM is based on a overall assessment clinical presentation, neuroimaging findings, and CSF examination, while CSF cytology remains the gold standard [3], and Fig. 1 presents representative radiographic and cytological features of LM.LM often presents with multifocal neurologic symptoms due to neuroaxis infiltration or raised intracranial pressure. Common manifestations include cranial neuropathies, headache, nausea and mental status changes, and spinal/cauda equina symptoms [4-5]. Even with interventions, outcomes remain dismal, and there is no established standard of care for LM. Management is generally palliative and multidisciplinary, often including radiotherapy to symptomatic sites, systemic therapy targeted at the primary tumor, and intrathecal chemotherapy to directly treat leptomeningeal disease [2, 6]. Given the rarity and lethality of LM, optimizing treatment strategies especially intrathecal chemotherapy to improve neurological outcomes and prolong survival is a pressing clinical challenge. Intrathecal chemotherapy is a key component of LM treatment, aimed at bypassing the blood–brain barrier to achieve therapeutic drug levels in the CSF [7]. Intrathecal therapy can be administered by two principal routes: repeated lumbar puncture (LP) injections into CSF, or via an Ommaya reservoir – a surgically implanted intraventricular catheter system that allows direct drug delivery into the lateral ventricle (schematic illustration in Fig. 2). Current evidence suggests that the use of an Ommaya reservoir may confer advantages in terms of treatment efficacy and prognosis [8-9]. Howerver most existing data are derived from single-center, small-sample observational studies , leading to inconsistent conclusions and insufficient high-quality evidence to guide clinical practice. To fill this evidence gap, and provide evidence-based support, we systematically synthesized the available data, aiming to determine whether intrathecal delivery approach offers a significant advantage in prolonging survival or achieving CSF disease control. Clarifying the relative benefits and limitations of intraventricular chemotherapy via Ommaya reservoir versus intrathecal chemotherapy via lumbar puncture will provide valuable evidence to guide clinical decision-making and may help optimize treatment strategies for patients suffering from this challenging and lethal complication of cancer. Methods Search strategy We conducted a systematic search of MEDLINE, PubMed, and the web of science for relative literature between 1986 and 2026. A comprehensive literature search was conducted to retrieve all eligible published and unpublished primary studies. The following search terms were used: ‘leptomeningeal metastasis or meningeal carcinomatosis’, ‘leptomeningeal metastasis and mmaya reservoir’, ‘leptomeningeal metastasis and intrathecal’. We screened the titles and abstracts of the retrieved literature and extracted all observational studies. Potentially eligible articles were independently assessed by two reviewers. Furthermore, the reference lists of all included studies were manually checked to identify additional potentially relevant publications. The search was restricted to human studies and articles published in English. Inclusion/exclusion criteria Studies were considered eligible for inclusion if they satisfied the following criteria. For meta-analysis: 1) a comparison between fully intrathecal injection with Ommaya reservoir and with lumbar puncture; 2) each compared group included 8 or more patients who had undergone chemotherapy in the same center. For generalized linear mixed model (GLMM) analysis: 1) single-arm study contucting IT injecetcion with Ommaya reservoir or lumbar puncture; 2) each group included 10 or more patients who had undergone chemotherapy in the same center. The exclusion criteria were as follows. For meta-analysis and generalized linear mixed model (GLMM) analysis: 1) non-investigative studies (case report, letters, and comments); 2) study that not specify the method of intrathecal injection, non-human studies. Methodological quality The risk of bias of the included non-randomized comparative studies was assessed using the Risk Of Bias In Non-randomized Studies – of Interventions, Version 2 (ROBINS‑I V2). Statistical analysis Review Manager, version 5.4 was used for meta-analysis. All outcomes assessed in the present study were dichotomous; thus, event rates along with their corresponding 95% confidence interval (CI) are presented. We used odds ratio (OR) and hazards ratio (HR) as summary statistic. OR > 1 for DCR favor Ommaya reservoir, whereas HR < 1 for OS favor Ommaya reservoir. For each meta-analysis, heterogeneity was evaluated using the Chi-square test and the I² statistic. A fixed-effects model was employed in the absence of heterogeneity ( p > 0.05, I² = 0%) or in cases of minimal heterogeneity ( p > 0.05, I² < 25%). Conversely, a random-effects model was adopted when substantial heterogeneity was observed ( p 50%). The incidence of adverse events was analyzed using a generalized linear mixed model (GLMM) with a logit link function, and differences were considered statistically significant if the p value was < 0.05. Furthermore, potential publication and selection bias affecting the pooled estimates was assessed using both the Harbord-Egger test and the Begg-Mazumdar test. A two-sided p value of less than 0.05 was regarded as statistically significant. Results Study Selection and Characteristics Four two-arm studies were identified for the head-to-head comparison of intrathecal chemotherapy delivered via an Ommaya reservoir versus lumbar puncture (LP) [11-14], and the characteristics were listed in Table 1. Because outcome reporting was inconsistent across studies, meta-analysis were performed only when a common effect measure could be derived. Accordingly, DCR was pooled as odds ratio (OR) using the Mantel–Haenszel method, and overall survival (OS) was pooled as hazard ratio (HR) using the inverse-variance approach. Table 1 Characteristic of Pooled Studies for Meta-analysis Study Publication year Study type Ommaya LP Ommaya LP Ommaya LP Lecoangeli et al. [11] 1995 Retrospective study 9 12 0.89 0.33 35.4 3.2 Hitchchins et al. [12] 1987 Prospective study 17 25 0.64 0.48 2.1 2 Montes et al. [13] 2018 Retrospective study 10 30 - 9.2 4 Kwon et al. [14] 2020 Retrospective study 66 35 0.44 0.46 - LP, Lumbar Puncture; DCR, Disease Control Rate; OS, Overall Survival Disease Control Rate The result of meta-analysis was shown in fig. 4. DCR was reported in three studies [11, 12, 14]. Given the small number of studies and the variation in study-level effects, a fixed-effect Mantel–Haenszel model was applied as prespecified in RevMan output, with heterogeneity quantified using I 2 . The pooled estimate did not demonstrate a statistically significant difference in DCR between Ommaya and LP administration (OR 1.43; 95% CI, 0.76–2.68, p =0.27). Notably, between-study heterogeneity was moderate-to-substantial (Chi² = 5.83, df = 2, p = 0.05; I 2 = 66%), indicating that DCR effects were not consistent across studies. Taken together, these data suggest that evidence for superior disease control with Ommaya versus LP remains inconclusive based on available comparative studies, and any apparent differences in individual cohorts should be interpreted cautiously in light of heterogeneity and imprecision. Overall Survival Three studies contributed data suitable for time-to-event synthesis as HR [11, 13, 14], and a random-effects inverse-variance model was used to account for potential clinical differences across cohorts and treatment eras. The pooled analysis showed a significant OS benefit favoring Ommaya delivery over LP (HR 0.39; 95% CI, 0.25–0.61, p <0.0001). Statistical heterogeneity was negligible (Tau²=0.00; Chi² = 1.44, df = 2, p = 0.49; I 2 =0%), supporting the robustness and consistency of the observed survival advantage across the included studies. Consistent with the meta-analytic findings, descriptive medians generally trended toward longer OS in the Ommaya group , though median-based comparisons should be interpreted as supportive rather than definitive given differences in follow-up and censoring. Table 2 Characteristics of Pooled Studies for GLMM (logit link) analysis Name Study type Patients Delivery type Adverse events Li et al. [15] Prospective study 23 OR 2 patients experienced grade 3 or higher AEs, and 8 patients experienced grade 2 or lower AEs. Harahsheh et al. [16] Retrospective study 22 OR No patient experienced grade 3 or higher AEs, and 5 patient experienced grade 2 or lower AEs. Geng et al. [17] Retrospective study 34 LP No patients experienced grade 3 or higher AEs, and 8 patients experienced grade 2 or lower AEs. Zhong et al. [18] Retrospective study 31 LP 4 patients experienced grade 3 or higher AEs, and at least 15 patients experienced grade 2 or lower AEs. Li et al. [19] Prospective study 50 LP 12 patients experienced grade 3 or higher AEs, and 20 patients experienced grade 2 or lower AEs. Pan et al. [20] Prospective study 13 LP 6 patients experienced grade 3 or higher AEs, and 4 patients experienced grade 2 or lower AEs. OR, Ommaya Reservoir; LP, Lumbar Puncture; AEs, Aderse Events Safety Analysis Following the comparative meta-analyses of dualarm studies , we additionally assessed treatment tolerability using a broader evidence base. Because adverse events (AEs) were sparsely and inconsistently reported in the head-to-head studies, and because several relevant cohorts were available only as single-arm series, we conducted a separate analysis incorporating singlearm data to compare AE risk between administration routes. There were six single-arm cohorts pooled in our analysis. The characteristics of pooled studies were listed in Table 2. Specifically, two cohorts evaluated intrathecal/intraventricular chemotherapy delivered via an Ommaya reservoir, and four cohorts evaluated delivery via lumbar puncture [15-20]. For each cohort, we extracted the number of AEs and we specifically quantified AEs of grade 3 or higher, to investigate the safety disparities between Ommaya reservoir and lumbar puncture. The model-based predicted probabilities of overall and grade ≥ 3 adverse events according to administration route are shown in Fig. 5. Using a binomial generalized linear mixed model with a logit link and a study-level random intercept, we compared adverse-event risks between Ommaya administration and lumbar puncture (LP) across studies. For overall adverse events, the model-based predicted probability was 33.3% for Ommaya versus 53.9% for LP, corresponding to an odds ratio (OR) of 0.43 (95% CI 0.21–0.87, p = 0.0191). For grade 3 or higher adverse events, the predicted probability was 4.4% for Ommaya versus 17.2% for LP (OR = 0.22; 95% CI 0.05–0.99, p = 0.0491). Overall, the point estimates suggested lower rates of both overall and severe adverse events with Ommaya compared with LP, although these results should be interpreted with caution given the limited number of Ommaya studies and the potential between-study heterogeneity inherent to across-study comparisons. Discussion Principal Findings Leptomeningeal metastasis (LM) remains a devastating complication of advanced cancer, characterized by dissemination of malignant cells within the leptomeninges and cerebrospinal fluid (CSF), leading to multifocal neurologic deficits, impaired CSF circulation, and a persistently poor prognosis despite multimodality care. The optimal route of intrathecal administration—repeated lumbar puncture (LP) versus intraventricular delivery via an implanted reservoir (Ommaya)—is clinically important, because route selection affects feasibility of repeated dosing, monitoring, and potentially drug distribution and efficacy. Recent expert guidance from the EANO–ESMO Clinical Practice Guideline and consensus of Chinese expert explicitly state that intrathecal chemotherapy should be delivered via the ventricular route when possible [21-22], reflecting both practical and pharmacologic considerations. In our synthesis of comparative studies, intraventricular administration via an Ommaya reservoir was associated with a statistically significant overall survival (OS) advantage compared with LP (pooled HR 0.39), with negligible statistical heterogeneity. In contrast, disease control rate (DCR) did not significantly differ between routes (pooled OR 1.43) and showed moderate-to-substantial heterogeneity. Clinically, these findings suggest that route choice may be more consistently reflected in time-to-event outcomes (OS) than in DCR, and that the survival association observed with Ommaya delivery is unlikely to be driven solely by short-interval ‘disease control’ as variably defined across studies. Interpretation of Survival and Disease Control Findings Several factors may explain why OS appears more sensitive to route than DCR. First, OS is a relatively objective endpoint, whereas DCR in LM can be operationalized in heterogeneous ways (clinical symptoms, MRI interpretation, CSF cytology, or composite measures), assessed at nonuniform time points, and influenced by the intrinsic difficulty of evaluating LM response. This is precisely why the Response Assessment in Neuro-Oncology (RANO) LM group proposed standardized response criteria and an MRI scorecard, acknowledging that most LM lesions are nonmeasurable and imaging assessment can be subjective [23]. Second, OS integrates downstream benefits that may not be captured by early DCR, including sustained treatment delivery, fewer interruptions, and improved capacity for longitudinal monitoring and timely escalation of therapy.Third, the observed OS advantage may also be influenced by unmeasured procedure-related factors. In some patients, Ommaya reservoir placement may facilitate concomitant CSF drainage interventions, such as ventriculoperitoneal shunting or repeated CSF aspiration, which could relieve intracranial hypertension and improve neurological status. Because such information was not consistently available in the included studies, residual confounding cannot be fully excluded, and prospective studies are needed to confirm whether the OS benefit is truly attributable to the administration route itself. Potential Advantages of Ommaya Delivery Route-dependent CSF pharmacokinetics and distribution have long been recognized. In a classic study, Shapiro and colleagues examined methotrexate kinetics after intravenous infusion, intraventricular administration via an Ommaya reservoir, and intralumbar injection, demonstrating route-related differences in CSF exposure and distribution patterns and suggesting a potential distribution advantage with Ommaya-based intraventricular delivery [8]. Preclinical and translational data suggest that drug distribution after intralumbar intrathecal dosing may be incomplete and variable, whereas intraventricular delivery (via an Ommaya reservoir) can provide a more controllable and more predictable CSF exposure profile, with ventricular-to-spinal concentration gradients shaped by CSF transport and flow dynamics [24-26]. Beyond pharmacology, Ommaya delivery can improve the feasibility of repeated intrathecal dosing and serial CSF sampling, reducing dependence on repeated LPs that may be limited by patient discomfort, challenging anatomy, thrombocytopenia, procedural delays, or post-dural puncture headache [27]. The practical advantage of reliable access may translate into fewer missed or delayed doses and more consistent monitoring [9] — mechanisms that could plausibly influence OS even when early disease control signals are inconsistent. In real-world cohorts, Ommaya-based access has been reported as safe and feasible for both treatment and frequent disease monitoring in eligible patients [16]. Overall, the low procedural risk of Ommaya reservoir placement, improved patient adherence [16, 26], and the convenience of repeated cerebrospinal fluid monitoring may be important factors contributing to the longer overall survival observed in patients treated via the Ommaya route. Safety Considerations Safety is central to route selection, and it is also an area where comparative data are frequently incomplete. To address this, we conducted a separate across-study analysis incorporating six single-arm cohorts (two Ommaya cohorts, four LP cohorts) and compared adverse-event risks between routes using a binomial generalized linear mixed model (logit link) with a study-level random intercept. This approach was selected to leverage single-arm evidence while partially accounting for between-study heterogeneity. Our model-based estimates suggested lower predicted probabilities of AEs with Ommaya administration than with LP, confidence intervals were wide — likely reflecting limited information (few Ommaya cohorts) and heterogeneity across studies. Clinically, these findings should be interpreted as supportive rather than definitive, because across-study comparisons of single-arm series remain vulnerable to confounding by baseline risk, systemic therapy backbones, dosing schedules, monitoring intensity, and AE ascertainment. However, device- and procedure- related risks of Ommaya reservoir placement should also be considered. In a series of patients with leptomeningeal metastases, placement-related complications were reported in 9.3% of cases, including infection, catheter malposition, and intracranial hemorrhage [26]. In a large 16-year institutional analysis of 616 patients, Ommaya reservoir infection occurred in 5.5% of patients, highlighting infection as one of the most clinically relevant device-related complications [28]. Overall, these data suggest that Ommaya placement is associated with a non-negligible but generally acceptable procedural risk in appropriately selected patients. Therefore, although the potential survival and treatment-delivery advantages of ventricular access remain important, the decision to use an Ommaya reservoir should still take into account neurosurgical expertise, peri-procedural management, and the patient’s bleeding and infection risk profile [21, 29]. Clinical Implications Taken together, our results support a pragmatic, clinically oriented inference: for LM patients who are candidates for neurosurgical implantation and who are expected to require repeated intra-CSF dosing and frequent CSF monitoring, intraventricular delivery via Ommaya is a reasonable — and often preferable — route, consistent with EANO–ESMO guidance. Nonetheless, route selection should remain individualized, incorporating performance status, anticipated survival, platelet/coagulation status, hydrocephalus and CSF flow patterns, burden of systemic disease, concomitant radiotherapy/systemic therapies, and patient preference. Strenths and limitations A key strength of this work is its route-focused synthesis using appropriate effect measures for each endpoint (OR for DCR and HR for OS), combined with a model-based tolerability analysis that explicitly incorporates between-study variability. However, our limitations are substantial: the comparative evidence base remains small; studies span different tumor types, drug regimens, and treatment eras; and selection bias is likely, as patients receiving Ommaya reservoirs may differ systematically from those treated via LP. DCR heterogeneity further limits certainty and reinforces the need for standardized endpoints and adoption of RANO LM response criteria in future trials [23]. Futrue Directions Future research should prioritize prospective, multi-center designs that better isolate the effect of route from confounding — potentially via pragmatic trials, or robust observational methods such as target-trial emulation and propensity-based approaches. Studies should standardize (1) route-specific technique (including intraventricular injection protocols), (2) response endpoints (RANO LM criteria), (3) CSF flow assessment strategies, and (4) comprehensive device-related complication reporting. Finally, given ongoing debate about the role and optimal integration of intrathecal therapy in the era of effective systemic agents, balanced appraisals of indications and patient selection remain critical [7]. Conclusion In summary, our comparative suggests that Ommaya-based intraventricular delivery of intrathecal chemotherapy is associated with improved OS compared with LP, while evidence for superior DCR remains inconclusive and heterogeneous. A complementary single-arm, across-study analysis suggested lower AEs rates with Ommaya delivery. These findings reinforce guideline-consistent consideration of intraventricular delivery for eligible patients requiring repeated intrathecal therapy, and they highlight the need for prospective, standardized studies integrating CSF flow dynamics, modern systemic therapy backbones, and rigorous safety reporting. Declarations Supplementary information None. Acknowledgements None. Author contributions Study conception and design: Lushao Zhang, Mingtao Feng, Yuechao Yang. Data collection and data analysis: Lushao Zhang, Mingtao Feng, Yuechao Yang, Zhe Qi, Pokherel Bihani, Kazmi Sabrina Shah, Yu Xuan Ong, Kexuan Wang, Yiqun Cao, Liangdong Li, Yang Gao. Manuscript drafting: Lushao Zhang, Mingtao Feng, Yuechao Yang. Manuscript revision: Lushao Zhang, Mingtao Feng, Yuechao Yang, Yiqun Cao, Liangdong Li, Yang Gao. All author carefully reviewed and approved the final manuscripit. Funding The authors received no specific funding for this work. Date availability The datasets analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Authors and Affiliations Lushao Zhang 1,2 † · Mingtao Feng 1,2 † · Yuechao Yang 1,2 † · Zhe Qi 1,2 · Pokharel Bihani 1,2 · Kazmi Sabrina Shah 1,2 · Yu Xuan Ong 1,2 · Kexuan Wang 1,2 · Yiqun Cao 1,2* · Liangdong Li 1,2* · Yang Gao 1,2* Department of Neurosugery, Fudan University Shanghai Cancer Center, Shanghai 200032, China Department of Oncology, Shanghai Medical Colledge, Fudan University, Shanghai 200032, China。 *Crrespondence: Yang Gao ( [email protected] ), Liangdong Li ( [email protected] ), Yiqun Cao ( [email protected] ). † Lushao Zhang, Mingtao Feng, and Yuechao Yang are co-first authors. 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Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 09 May, 2026 Reviews received at journal 29 Apr, 2026 Reviews received at journal 29 Apr, 2026 Reviews received at journal 28 Apr, 2026 Reviewers agreed at journal 27 Apr, 2026 Reviewers agreed at journal 24 Apr, 2026 Reviewers agreed at journal 23 Apr, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers invited by journal 21 Apr, 2026 Editor assigned by journal 21 Apr, 2026 Submission checks completed at journal 21 Apr, 2026 First submitted to journal 20 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9469387","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":631267662,"identity":"0cae71d3-e414-4182-96c8-8b3d77688ab5","order_by":0,"name":"Lushao Zhang","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Lushao","middleName":"","lastName":"Zhang","suffix":""},{"id":631267664,"identity":"23d4122b-6487-4ae3-b8f9-308b552262a8","order_by":1,"name":"Mingtao Feng","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Mingtao","middleName":"","lastName":"Feng","suffix":""},{"id":631267666,"identity":"c1ed2f1d-1049-4c88-876f-3f4ba0cbac68","order_by":2,"name":"Yuechao Yang","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Yuechao","middleName":"","lastName":"Yang","suffix":""},{"id":631267667,"identity":"1afc90dc-7707-4e2e-a23d-a42b8a78184b","order_by":3,"name":"Zhe Qi","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Qi","suffix":""},{"id":631267669,"identity":"4e802c19-775a-4439-808c-42aee74f7cc8","order_by":4,"name":"Bihani Pokharel","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Bihani","middleName":"","lastName":"Pokharel","suffix":""},{"id":631267671,"identity":"200d0674-41c3-466c-9a9d-4a1dea0ef2db","order_by":5,"name":"Sabrina Kazmi Shah","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Sabrina","middleName":"Kazmi","lastName":"Shah","suffix":""},{"id":631267673,"identity":"74e5f408-40d6-43e8-a3bd-4925c29be422","order_by":6,"name":"Yu Xuan Ong","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"Xuan","lastName":"Ong","suffix":""},{"id":631267674,"identity":"8517a1ef-f2dc-4bf8-95dc-49a15018d59a","order_by":7,"name":"Kexuan Wang","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Kexuan","middleName":"","lastName":"Wang","suffix":""},{"id":631267675,"identity":"67456464-dfba-407d-b1de-1433bab7e115","order_by":8,"name":"Yiqun Cao","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Yiqun","middleName":"","lastName":"Cao","suffix":""},{"id":631267676,"identity":"6ce27711-6097-40f1-944c-32a5bc115ed2","order_by":9,"name":"Liangdong Li","email":"","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Liangdong","middleName":"","lastName":"Li","suffix":""},{"id":631267679,"identity":"8927bb14-3672-435c-aa2b-8938c309f100","order_by":10,"name":"Yang Gao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYDCCAzAGe2Pjgw+kaeE53Gw4gzQtEult0hzE6OC7fcbwc8GvWnl+yYcN0gwMdnK6DQS0SJ7LMZae2XfccObsxAbjAoZkY7MDBLQYnOExkObtOca44XZiQ/IMhgOJ24jQYvwbqMV+w82DDYd5iNRiJs3zoyZxww3GxmaitEieYSuz5m04kDyzJ7GZcYYBEX7hO8O8+TbPnzrbfvbjz398qLCTI6iFgYHDgIGx7TDMnQSVgwD7AwaGP3VEKR0Fo2AUjIIRCgDQzUjtWT0voAAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Oncology, Shanghai Medical Colledge, Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Yang","middleName":"","lastName":"Gao","suffix":""}],"badges":[],"createdAt":"2026-04-20 08:53:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9469387/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9469387/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108183311,"identity":"dad94287-579e-4a91-9000-6453573a8bcb","added_by":"auto","created_at":"2026-04-30 09:00:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":62505509,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative radiologic and cytologic findings of leptomeningeal metastasis.\u003c/p\u003e\n\u003cp\u003e(A) Contrast-enhanced brain magnetic resonance imaging showing typical sulcal linear enhancement, suggestive of leptomeningeal involvement. (B) Cerebrospinal fluid cytology demonstrating malignant tumor cells.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-9469387/v1/3d7ff408f6352e19596079b7.png"},{"id":108183808,"identity":"aa1cc240-d0a4-4c31-83a6-85996b1f25ae","added_by":"auto","created_at":"2026-04-30 09:02:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":15666875,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of the comparison between Ommaya chemotherapy and lumbar puncture chemotherapy\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-9469387/v1/c31d74cbec5a4e7dfcc41bd7.png"},{"id":108184214,"identity":"487c2f4b-f56f-494f-b374-7f43ba0ac4bb","added_by":"auto","created_at":"2026-04-30 09:03:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":22401024,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart diagram of the study selection progress\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-9469387/v1/494861d95a5a4aae0d980cda.png"},{"id":108184186,"identity":"09d9ab17-9533-4caa-97e3-7482feaa31fa","added_by":"auto","created_at":"2026-04-30 09:03:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3929425,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot based on DCR and OS\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-9469387/v1/27ff96903d91bc1daac6acf4.png"},{"id":108183823,"identity":"a0283159-a07f-4829-b05c-91045b63af5a","added_by":"auto","created_at":"2026-04-30 09:02:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4514752,"visible":true,"origin":"","legend":"\u003cp\u003eModel-based predicted probabilities of adverse events according to administration route.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Predicted probability of overall adverse events derived from the binomial generalized linear mixed model (GLMM) with a logit link. \u003cstrong\u003e(B)\u003c/strong\u003e Predicted probability of grade 3 or higher adverse events derived from the same model.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-9469387/v1/11f082e7ff3c1563ffe98f3b.png"},{"id":108097708,"identity":"c55e2b57-7289-4c09-955a-b9f101c8a2a2","added_by":"auto","created_at":"2026-04-29 10:15:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":244322,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9469387/v1/a019055f-d5d4-462e-a789-837c17487c6c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Comparative Study of Ommaya Reservoir versus Lumbar Puncture for Intrathecal Chemotherapy in Patients with Leptomeningeal Metastasis Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLeptomeningeal metastasis(LM) is an lethal complication of advanced cancer, defined by the spread of maligant cells to the leptomeninges and cerebrospinal fluid (CSF). LM occurs in patients with metastatic solid tumors or hematologic cancers , especically in those with the breast, lung, or melanoma [1-2].The diagnosis of LM is based on a overall assessment clinical presentation, neuroimaging findings, and CSF examination, while\u0026nbsp;CSF cytology remains the gold standard [3], and Fig. 1 presents representative radiographic and cytological features of LM.LM often presents with multifocal neurologic symptoms due to neuroaxis infiltration or raised intracranial pressure. Common manifestations include cranial neuropathies, headache, nausea and mental status changes, and spinal/cauda equina symptoms [4-5]. Even with interventions, outcomes remain dismal, and there is no established standard of care for LM. Management is generally palliative and multidisciplinary, often including radiotherapy to symptomatic sites, systemic therapy targeted at the primary tumor, and intrathecal chemotherapy to directly treat leptomeningeal disease [2, 6]. Given the rarity and lethality of LM, optimizing treatment strategies especially intrathecal chemotherapy to improve neurological outcomes and prolong survival is a pressing clinical challenge.\u003c/p\u003e\n\u003cp\u003eIntrathecal chemotherapy is a key component of LM treatment, aimed at bypassing the blood–brain barrier to achieve therapeutic drug levels in the CSF [7]. Intrathecal therapy can be administered by two principal routes: repeated lumbar puncture (LP) injections into CSF, or via an Ommaya reservoir – a surgically implanted intraventricular catheter system that allows direct drug delivery into the lateral ventricle (schematic illustration in\u0026nbsp;Fig. 2). Current evidence suggests that the use of an Ommaya reservoir may confer advantages in terms of treatment efficacy and prognosis [8-9]. Howerver most existing data are derived from \u003cstrong\u003esingle-center, small-sample observational studies\u003c/strong\u003e,\u0026nbsp;leading to inconsistent conclusions and insufficient high-quality evidence to guide clinical practice. To fill this evidence gap, and provide evidence-based support, we systematically synthesized the available data, aiming\u0026nbsp;to determine whether intrathecal delivery approach offers a significant advantage in prolonging survival or achieving CSF disease control. Clarifying the relative benefits and limitations of intraventricular chemotherapy via Ommaya reservoir versus intrathecal chemotherapy via lumbar puncture will provide valuable evidence to guide clinical decision-making and may help optimize treatment strategies for patients suffering from this challenging and lethal complication of cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eSearch strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a systematic search of MEDLINE, PubMed, and the web of science for relative literature between 1986 and 2026. A comprehensive literature search was conducted to retrieve all eligible published and unpublished primary studies.\u0026nbsp;The following search terms were used: ‘leptomeningeal metastasis or\u0026nbsp;meningeal carcinomatosis’, ‘leptomeningeal metastasis and mmaya reservoir’, ‘leptomeningeal metastasis and intrathecal’.\u0026nbsp;We screened the titles and abstracts of the retrieved literature and extracted all observational studies. Potentially eligible articles were independently assessed by two reviewers. Furthermore, the reference lists of all included studies were manually checked to identify additional potentially relevant publications. The search was restricted to human studies and articles published in English.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion/exclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies were considered eligible for inclusion if they satisfied the following criteria. For meta-analysis: 1) a comparison between fully intrathecal injection with Ommaya reservoir and with lumbar puncture; 2) each compared group included 8 or more patients who had undergone chemotherapy in the same center. For generalized linear mixed model (GLMM) analysis: 1) single-arm study contucting IT injecetcion with Ommaya reservoir or lumbar puncture; 2) each group included 10 or more patients who had undergone chemotherapy in the same center. The exclusion criteria were as follows. For meta-analysis and generalized linear mixed model (GLMM) analysis: 1) non-investigative studies (case report, letters, and comments); 2) study that not specify the method of intrathecal injection, non-human studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodological quality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias of the included non-randomized comparative studies was assessed using the Risk Of Bias In Non-randomized Studies – of Interventions, Version 2 (ROBINS‑I V2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReview Manager, version 5.4 was used for meta-analysis. All outcomes assessed in the present study were dichotomous; thus, event rates along with their corresponding 95% confidence interval (CI) are presented. We used odds ratio (OR) and hazards ratio (HR) as summary statistic.\u0026nbsp;OR \u0026gt; 1 for DCR favor Ommaya reservoir, whereas HR \u0026lt; 1 for OS favor Ommaya reservoir.\u0026nbsp;For each meta-analysis, heterogeneity was evaluated using the Chi-square test and the I² statistic. A fixed-effects model was employed in the absence of heterogeneity (\u003cem\u003ep\u003c/em\u003e \u0026gt; 0.05, I² = 0%) or in cases of minimal heterogeneity (\u003cem\u003ep\u003c/em\u003e \u0026gt; 0.05, I² \u0026lt; 25%). Conversely, a random-effects model was adopted when substantial heterogeneity was observed (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, I² \u0026gt; 50%). The incidence of adverse events was analyzed using a generalized linear mixed model (GLMM) with a logit link function, and differences were considered statistically significant if the \u003cem\u003ep\u003c/em\u003e value was \u0026lt; 0.05. Furthermore, potential publication and selection bias affecting the pooled estimates was assessed using both the Harbord-Egger test and the Begg-Mazumdar test. A two-sided \u003cem\u003ep\u003c/em\u003e value of less than 0.05 was regarded as statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy Selection and Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour two-arm studies were identified for the head-to-head comparison of intrathecal chemotherapy delivered via an Ommaya reservoir versus lumbar puncture (LP) [11-14], and the characteristics were listed in Table 1. Because outcome reporting was inconsistent across studies, meta-analysis were performed only when a common effect measure could be derived. Accordingly, DCR was pooled as odds ratio (OR) using the Mantel\u0026ndash;Haenszel method, and overall survival (OS) was pooled as hazard ratio (HR) using the inverse-variance approach.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Characteristic of Pooled Studies for Meta-analysis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"694\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0288%;\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3919%;\"\u003e\n \u003cp\u003ePublication year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4006%;\"\u003e\n \u003cp\u003eStudy type\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1383%;\"\u003e\n \u003cp\u003eOmmaya \u0026nbsp; \u0026nbsp; \u0026nbsp;LP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.8588%;\"\u003e\n \u003cp\u003eOmmaya \u0026nbsp; \u0026nbsp; \u0026nbsp;LP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.1816%;\"\u003e\n \u003cp\u003eOmmaya \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;LP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0288%;\"\u003e\n \u003cp\u003eLecoangeli et al. [11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3919%;\"\u003e\n \u003cp\u003e1995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4006%;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1383%;\"\u003e\n \u003cp\u003e9 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.8588%;\"\u003e\n \u003cp\u003e0.89 \u0026nbsp; \u0026nbsp; \u0026nbsp;0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.1816%;\"\u003e\n \u003cp\u003e35.4 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0288%;\"\u003e\n \u003cp\u003eHitchchins et al. [12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3919%;\"\u003e\n \u003cp\u003e1987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4006%;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1383%;\"\u003e\n \u003cp\u003e17 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.8588%;\"\u003e\n \u003cp\u003e0.64 \u0026nbsp; \u0026nbsp; \u0026nbsp;0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.1816%;\"\u003e\n \u003cp\u003e2.1 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0288%;\"\u003e\n \u003cp\u003eMontes et al. [13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3919%;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4006%;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1383%;\"\u003e\n \u003cp\u003e10 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.8588%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.1816%;\"\u003e\n \u003cp\u003e9.2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0288%;\"\u003e\n \u003cp\u003eKwon et al. [14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3919%;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4006%;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.1383%;\"\u003e\n \u003cp\u003e66 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.8588%;\"\u003e\n \u003cp\u003e0.44 \u0026nbsp; \u0026nbsp; \u0026nbsp;0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.1816%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLP, Lumbar Puncture; DCR, Disease Control Rate; OS, Overall Survival\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisease Control Rate\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe result of meta-analysis was shown in fig. 4. DCR was reported in three studies [11, 12, 14]. Given the small number of studies and the variation in study-level effects, a fixed-effect Mantel\u0026ndash;Haenszel model was applied as prespecified in RevMan output, with heterogeneity quantified using I\u003csup\u003e2\u003c/sup\u003e. The pooled estimate did not demonstrate a statistically significant difference in DCR between Ommaya and LP administration (OR 1.43; 95% CI, 0.76\u0026ndash;2.68, \u003cem\u003ep\u003c/em\u003e=0.27). Notably, between-study heterogeneity was moderate-to-substantial (Chi\u0026sup2; = 5.83, df = 2, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.05; I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 66%), indicating that DCR effects were not consistent across studies. Taken together, these data suggest that evidence for superior disease control with Ommaya versus LP remains inconclusive based on available comparative studies, and any apparent differences in individual cohorts should be interpreted cautiously in light of heterogeneity and imprecision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall Survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree studies contributed data suitable for time-to-event synthesis as HR [11, 13, 14], and a random-effects inverse-variance model was used to account for potential clinical differences across cohorts and treatment eras. The pooled analysis showed a significant OS benefit favoring Ommaya delivery over LP (HR 0.39; 95% CI, 0.25\u0026ndash;0.61, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001). Statistical heterogeneity was negligible (Tau\u0026sup2;=0.00; Chi\u0026sup2; = 1.44, df = 2, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.49; I\u003csup\u003e2\u003c/sup\u003e=0%), supporting the robustness and consistency of the observed survival advantage across the included studies. Consistent with the meta-analytic findings, descriptive medians generally trended toward longer OS in the Ommaya group , though median-based comparisons should be interpreted as supportive rather than definitive given differences in follow-up and censoring.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eCharacteristics of Pooled Studies for GLMM (logit link) analysis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003eName\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eDelivery type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003eAdverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003eLi et al. [15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003e2 patients experienced grade 3 or higher AEs, and 8 patients experienced grade 2 or lower AEs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003eHarahsheh et al. [16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003eNo patient experienced grade 3 or higher AEs, and 5 patient experienced grade 2 or lower AEs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003eGeng et al. [17]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003eNo patients experienced grade 3 or higher AEs, and 8 patients experienced grade 2 or lower AEs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003eZhong et al. [18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003e4 patients experienced grade 3 or higher AEs, and at least 15 patients experienced grade 2 or lower AEs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003eLi et al. [19]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003e12 patients experienced grade 3 or higher AEs, and 20 patients experienced grade 2 or lower AEs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20.0284%;\"\u003e\n \u003cp\u003ePan et al. [20]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.7727%;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.94318%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4886%;\"\u003e\n \u003cp\u003eLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40.767%;\"\u003e\n \u003cp\u003e6 patients experienced grade 3 or higher AEs, and 4 patients experienced grade 2 or lower AEs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOR, Ommaya Reservoir; LP, Lumbar Puncture; AEs, Aderse Events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing the comparative meta-analyses of dualarm studies , we additionally assessed treatment tolerability using a broader evidence base. Because adverse events (AEs) were sparsely and inconsistently reported in the head-to-head studies, and because several relevant cohorts were available only as single-arm series, we conducted a separate analysis incorporating singlearm data to compare AE risk between administration routes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere were six single-arm cohorts pooled in our analysis. The characteristics of pooled studies were listed in Table 2. Specifically, two cohorts evaluated intrathecal/intraventricular chemotherapy delivered via an Ommaya reservoir, and four cohorts evaluated delivery via lumbar puncture [15-20]. For each cohort, we extracted the number of AEs and we specifically quantified AEs of grade 3 or higher, to investigate the safety disparities between Ommaya reservoir and lumbar puncture.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe model-based predicted probabilities of overall and grade \u0026ge; 3 adverse events according to administration route are shown in Fig. 5. Using a binomial generalized linear mixed model with a logit link and a study-level random intercept, we compared adverse-event risks between Ommaya administration and lumbar puncture (LP) across studies. For overall adverse events, the model-based predicted probability was 33.3% for Ommaya versus 53.9% for LP, corresponding to an odds ratio (OR) of 0.43 (95% CI 0.21\u0026ndash;0.87, \u003cem\u003ep\u003c/em\u003e = 0.0191). For grade 3 or higher adverse events, the predicted probability was 4.4% for Ommaya versus 17.2% for LP (OR = 0.22; 95% CI 0.05\u0026ndash;0.99, \u003cem\u003ep\u003c/em\u003e = 0.0491). Overall, the point estimates suggested lower rates of both overall and severe adverse events with Ommaya compared with LP, although these results should be interpreted with caution given the limited number of Ommaya studies and the potential between-study heterogeneity inherent to across-study comparisons.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003ePrincipal Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLeptomeningeal metastasis (LM) remains a devastating complication of advanced cancer, characterized by dissemination of malignant cells within the leptomeninges and cerebrospinal fluid (CSF), leading to multifocal neurologic deficits, impaired CSF circulation, and a persistently poor prognosis despite multimodality care. The optimal route of intrathecal administration—repeated lumbar puncture (LP) versus intraventricular delivery via an implanted reservoir (Ommaya)—is clinically important, because route selection affects feasibility of repeated dosing, monitoring, and potentially drug distribution and efficacy. Recent expert guidance from the EANO–ESMO Clinical Practice Guideline and consensus of Chinese expert explicitly state that intrathecal chemotherapy should be delivered via the ventricular route when possible [21-22], reflecting both practical and pharmacologic considerations.\u003c/p\u003e\n\u003cp\u003eIn our synthesis of comparative studies, intraventricular administration via an Ommaya reservoir was associated with a statistically significant overall survival (OS) advantage compared with LP (pooled HR 0.39), with negligible statistical heterogeneity. In contrast, disease control rate (DCR) did not significantly differ between routes (pooled OR 1.43) and showed moderate-to-substantial heterogeneity. Clinically, these findings suggest that route choice may be more consistently reflected in time-to-event outcomes (OS) than in DCR, and that the survival association observed with Ommaya delivery is unlikely to be driven solely by short-interval ‘disease control’ as variably defined across studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation of Survival and Disease Control Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral factors may explain why OS appears more sensitive to route than DCR. First, OS is a relatively objective endpoint, whereas DCR in LM can be operationalized in heterogeneous ways (clinical symptoms, MRI interpretation, CSF cytology, or composite measures), assessed at nonuniform time points, and influenced by the intrinsic difficulty of evaluating LM response. This is precisely why the Response Assessment in Neuro-Oncology (RANO) LM group proposed standardized response criteria and an MRI scorecard, acknowledging that most LM lesions are nonmeasurable and imaging assessment can be subjective [23]. Second, OS integrates downstream benefits that may not be captured by early DCR, including sustained treatment delivery, fewer interruptions, and improved capacity for longitudinal monitoring and timely escalation of therapy.Third, the observed OS advantage may also be influenced by unmeasured procedure-related factors. In some patients, Ommaya reservoir placement may facilitate concomitant CSF drainage interventions, such as ventriculoperitoneal shunting or repeated CSF aspiration, which could relieve intracranial hypertension and improve neurological status. Because such information was not consistently available in the included studies, residual confounding cannot be fully excluded, and prospective studies are needed to confirm whether the OS benefit is truly attributable to the administration route itself.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential Advantages of Ommaya Delivery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRoute-dependent CSF pharmacokinetics and distribution have long been recognized. In a classic study, Shapiro and colleagues examined methotrexate kinetics after intravenous infusion, intraventricular administration via an Ommaya reservoir, and intralumbar injection, demonstrating route-related differences in CSF exposure and distribution patterns and suggesting a potential distribution advantage with Ommaya-based intraventricular delivery [8]. Preclinical and translational data suggest that drug distribution after intralumbar intrathecal dosing may be incomplete and variable, whereas intraventricular delivery (via an Ommaya reservoir) can provide a more controllable and more predictable CSF exposure profile, with ventricular-to-spinal concentration gradients shaped by CSF transport and flow dynamics [24-26].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBeyond pharmacology, Ommaya delivery can improve the feasibility of repeated intrathecal dosing and serial CSF sampling, reducing dependence on repeated LPs that may be limited by patient discomfort, challenging anatomy, thrombocytopenia, procedural delays, or post-dural puncture headache [27]. The practical advantage of reliable access may translate into fewer missed or delayed doses and more consistent monitoring [9] — mechanisms that could plausibly influence OS even when early disease control signals are inconsistent. In real-world cohorts, Ommaya-based access has been reported as safe and feasible for both treatment and frequent disease monitoring in eligible patients [16].\u0026nbsp;Overall, the low procedural risk of Ommaya reservoir placement, improved patient adherence [16, 26], and the convenience of repeated cerebrospinal fluid monitoring may be important factors contributing to the longer overall survival observed in patients treated via the Ommaya route.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSafety is central to route selection, and it is also an area where comparative data are frequently incomplete. To address this, we conducted a separate across-study analysis incorporating six single-arm cohorts (two Ommaya cohorts, four LP cohorts) and compared adverse-event risks between routes using a binomial generalized linear mixed model (logit link) with a study-level random intercept. This approach was selected to leverage single-arm evidence while partially accounting for between-study heterogeneity.\u003c/p\u003e\n\u003cp\u003eOur model-based estimates suggested lower predicted probabilities of AEs with Ommaya administration than with LP, confidence intervals were wide — likely reflecting limited information (few Ommaya cohorts) and heterogeneity across studies. Clinically, these findings should be interpreted as supportive rather than definitive, because across-study comparisons of single-arm series remain vulnerable to confounding by baseline risk, systemic therapy backbones, dosing schedules, monitoring intensity, and AE ascertainment.\u003c/p\u003e\n\u003cp\u003eHowever, device- and procedure- related risks of Ommaya reservoir placement should also be considered. In a series of patients with leptomeningeal metastases, placement-related complications were reported in 9.3% of cases, including infection, catheter malposition, and intracranial hemorrhage [26]. In a large 16-year institutional analysis of 616 patients, Ommaya reservoir infection occurred in 5.5% of patients, highlighting infection as one of the most clinically relevant device-related complications [28]. Overall, these data suggest that Ommaya placement is associated with a non-negligible but generally acceptable procedural risk in appropriately selected patients. Therefore, although the potential survival and treatment-delivery advantages of ventricular access remain important, the decision to use an Ommaya reservoir should still take into account neurosurgical expertise, peri-procedural management, and the patient’s bleeding and infection risk profile [21, 29].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Implications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTaken together, our results support a pragmatic, clinically oriented inference: for LM patients who are candidates for neurosurgical implantation and who are expected to require repeated intra-CSF dosing and frequent CSF monitoring, intraventricular delivery via Ommaya is a reasonable — and often preferable — route, consistent with EANO–ESMO guidance. Nonetheless, route selection should remain individualized, incorporating performance status, anticipated survival, platelet/coagulation status, hydrocephalus and CSF flow patterns, burden of systemic disease, concomitant radiotherapy/systemic therapies, and patient preference.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrenths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA key strength of this work is its route-focused synthesis using appropriate effect measures for each endpoint (OR for DCR and HR for OS), combined with a model-based tolerability analysis that explicitly incorporates between-study variability. However, our limitations are substantial: the comparative evidence base remains small; studies span different tumor types, drug regimens, and treatment eras; and selection bias is likely, as patients receiving Ommaya reservoirs may differ systematically from those treated via LP. DCR heterogeneity further limits certainty and reinforces the need for standardized endpoints and adoption of RANO LM response criteria in future trials [23].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFutrue Directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFuture research should prioritize prospective, multi-center designs that better isolate the effect of route from confounding — potentially via pragmatic trials, or robust observational methods such as target-trial emulation and propensity-based approaches. Studies should standardize (1) route-specific technique (including intraventricular injection protocols), (2) response endpoints (RANO LM criteria), (3) CSF flow assessment strategies, and (4) comprehensive device-related complication reporting. Finally, given ongoing debate about the role and optimal integration of intrathecal therapy in the era of effective systemic agents, balanced appraisals of indications and patient selection remain critical [7].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our comparative suggests that Ommaya-based intraventricular delivery of intrathecal chemotherapy is associated with improved OS compared with LP, while evidence for superior DCR remains inconclusive and heterogeneous. A complementary single-arm, across-study analysis suggested lower AEs rates with Ommaya delivery. These findings reinforce guideline-consistent consideration of intraventricular delivery for eligible patients requiring repeated intrathecal therapy, and they highlight the need for prospective, standardized studies integrating CSF flow dynamics, modern systemic therapy backbones, and rigorous safety reporting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eStudy conception and design: Lushao Zhang, Mingtao Feng, Yuechao Yang. Data collection and data analysis: \u0026nbsp;Lushao Zhang, Mingtao Feng, Yuechao Yang, Zhe Qi, Pokherel Bihani, Kazmi Sabrina Shah, Yu Xuan Ong, Kexuan Wang, Yiqun Cao, Liangdong Li, Yang Gao. Manuscript drafting: Lushao Zhang, Mingtao Feng, Yuechao Yang. Manuscript revision: Lushao Zhang, Mingtao Feng, Yuechao Yang, Yiqun Cao, Liangdong Li, Yang Gao. All author carefully reviewed and approved the final manuscripit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThe authors received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDate availability\u0026nbsp;\u003c/strong\u003eThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLushao Zhang\u003csup\u003e1,2\u003c/sup\u003e\u003c/strong\u003e\u003csup\u003e†\u003c/sup\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eMingtao Feng\u003csup\u003e1,2\u003c/sup\u003e\u003c/strong\u003e\u003csup\u003e†\u003c/sup\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eYuechao Yang\u003csup\u003e1,2\u003c/sup\u003e\u003c/strong\u003e\u003csup\u003e†\u003c/sup\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eZhe Qi\u003csup\u003e1,2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePokharel Bihani\u003csup\u003e1,2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eKazmi Sabrina Shah\u003csup\u003e1,2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eYu Xuan Ong\u003csup\u003e1,2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eKexuan Wang\u003csup\u003e1,2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eYiqun Cao\u003csup\u003e1,2*\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eLiangdong Li\u003csup\u003e1,2*\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e·\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eYang Gao\u003csup\u003e1,2*\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eDepartment of Neurosugery, Fudan University Shanghai Cancer Center, Shanghai 200032, China\u003c/li\u003e\n \u003cli\u003eDepartment of Oncology, Shanghai Medical Colledge, Fudan University, Shanghai 200032, China。\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e*Crrespondence: Yang Gao ([email protected]), Liangdong Li ([email protected]), Yiqun Cao ([email protected]).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e†\u003c/sup\u003eLushao Zhang, Mingtao Feng, and Yuechao Yang are co-first authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKaplan JG, DeSouza TG, Farkash A, Shafran B, Pack D, Rehman F, Fuks J, Portenoy R (1990 Dec) Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. 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J Neurol Sci 223(2):167-78\u003c/li\u003e\n\u003cli\u003eEmilie Le Rhun, Barbara J O\u0026rsquo;Brien, Elena Pentsova, Matthias Preusser, Michael Weller, Adrienne Boire (Oct 2025 14) Point/Counterpoint: Intrathecal therapy for patients with leptomeningeal metastases from solid tumors.\u0026nbsp;Neuro Oncol 27(9):2225-2231\u003c/li\u003e\n\u003cli\u003eShapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med. 1975 Jul 24;\u003c/li\u003e\n\u003cli\u003eGlantz MJ, Chamberlain MC, Batchelor, T., Eric W, Cavalli F, Shapiro WR (2006 Jun) Interaction between route of intra-CSF chemotherapy administration and efficacy of therapy in patients wtih neoplastic meningitis. J Clin Oncol 24(18): 1530\u0026ndash;1530\u003c/li\u003e\n\u003cli\u003eHiggins JPT, Morgan RL, Rooney AA, Taylor KW, Thayer KA, Silva RA, Lemeris C, Akl EA, Bateson TF, Berkman ND, Glenn BS, Hr\u0026oacute;bjartsson A, LaKind JS, McAleenan A, Meerpohl JJ, Nachman RM, Obbagy JE, O'Connor A, Radke EG, Savović J, Sch\u0026uuml;nemann HJ, Shea B, Tilling K, Verbeek J, Viswanathan M, Sterne JAC (2024) A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environment International 186:108602 Avalable at https://doi.org/10.1016/j.envint.2024.108602\u003c/li\u003e\n\u003cli\u003eIacoangeli M, Roselli R, Pagano L, Leone G, Marra R, Pompucci A, Trignani R, Scerrati M (1995 Apr) Intrathecal chemotherapy for treatment of overt meningeal leukemia: comparison between intraventricular and traditional intralumbar route. Ann Oncol 6(4):377-82\u003c/li\u003e\n\u003cli\u003eHitchins RN, Bell DR, Woods RL, Levi JA (1987 Oct) A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 5(10):1655-62\u003c/li\u003e\n\u003cli\u003eMontes de Oca Delgado M, Cacho D\u0026iacute;az B, Santos Zambrano J, Guerrero Ju\u0026aacute;rez V, L\u0026oacute;pez Mart\u0026iacute;nez MS, Castro Mart\u0026iacute;nez E, Avenda\u0026ntilde;o M\u0026eacute;ndez-Padilla J, Mej\u0026iacute;a P\u0026eacute;rez S, Reyes Moreno I, Guti\u0026eacute;rrez Aceves A, Gonz\u0026aacute;lez Aguilar A (2018 Nov 20) The Comparative Treatment of Intraventricular Chemotherapy by Ommaya Reservoir vs. Lumbar Puncture in Patients With Leptomeningeal Carcinomatosis. Front Oncol 8:509\u003c/li\u003e\n\u003cli\u003eKwon BS, Cho YH, Yoon SK, Lee DH, Kim SW, Kwon DH, Lee JC, Choi CM (2020 Feb) Impact of clinicopathologic features on leptomeningeal metastasis from lung adenocarcinoma and treatment efficacy with epidermal growth factor receptor tyrosine kinase inhibitor. Thorac Cancer 11(2)：436-442\u003c/li\u003e\n\u003cli\u003eLi H, Zheng S, Lin Y, Yu T, Xie Y, Jiang C, Liu X, Qian X, Yin Z. (2023 Mar) 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. Clin Lung Cancer 24(2):e94-e104\u003c/li\u003e\n\u003cli\u003eHarahsheh E, Shah S, Butterfield RJ, Ariete CC, Yancey EJ, Meyer JH, Lyons MK, Krishna C, Fortin-Ensign S, Zimmerman RS, Bendok BR, Mrugala MM (2025 Nov 5) Safety and feasibility of Ommaya reservoir for intrathecal chemotherapy in patients with leptomeningeal disease. Neurol Neurochir Pol 60(1):75-82\u003c/li\u003e\n\u003cli\u003eGeng D, Guo Q, Huang S, Zhang H, Guo S, Li X (2022 Jan-Dec) A Retrospective Study of Intrathecal Pemetrexed Combined With Systemic Therapy for Leptomeningeal Metastasis of Lung Cancer. Technol Cancer Res Treat 21:15330338221078429\u003c/li\u003e\n\u003cli\u003eZhong W, Wu L, Qiu Z, Yu W, Liu L, Shi H, Wu S (2025 Apr 7) Intrathecal pemetrexed chemotherapy combined with systemic therapy in patients with non-small cell lung cancer and leptomeningeal metastases: a retrospective study. Front Oncol 15:1545174\u003c/li\u003e\n\u003cli\u003eLi L, Huang Z, Chen Y, Ma H, Chen X, Yan H, Qin H, Zhang Y, Zhang X, Jiang W, Wang Z, Zhang L, Zeng F, Zhou Z, Pu X, Yang N, Zeng L, Zhang Y (2024 Dec 7) Intrathecal pemetrexed improves survival outcomes in previously treated EGFR-mutant advanced non-small-cell lung cancer with leptomeningeal metastases. Heliyon 10(24):e40703\u003c/li\u003e\n\u003cli\u003ePan Z, Yang G, Cui J, Li W, Li Y, Gao P, Jiang T, Sun Y, Dong L, Song Y, Zhao G (2019 Aug 30) A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. Front Oncol 9:838\u003c/li\u003e\n\u003cli\u003eLe Rhun E, Weller M, van den Bent M, Brandsma D, Furtner J, Rud\u0026agrave; R, Schadendorf D, Seoane J, Tonn JC, Wesseling P, Wick W, Minniti G, Peters S, Curigliano G, Preusser M (2023 Oct) EANO Guidelines Committee and ESMO Guidelines Committee. Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open 8(5):101624\u003c/li\u003e\n\u003cli\u003eLin G, Wang Y, Xin T, Zhang D, Zhang Q, Li Y, Chi Y, Fan Y, Liu A, Xu H, Shi L, Zhang L, Miao Q, Zheng X, Li L, Zhou K, Yao Q, Zou Z, Miao K, Hong Y (2025 Jun) Chinese Expert Consensus on Leptomeningeal Metastases of Lung Cancer. Thorac Cancer 16(11):e70088\u003c/li\u003e\n\u003cli\u003eChamberlain M, Junck L, Brandsma D, Soffietti R, Rud\u0026agrave; R, Raizer J, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Walker J, van den Bent M, Wen PY, Jaeckle KA (2017 Apr 1) Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol 19(4):484-492\u003c/li\u003e\n\u003cli\u003eBalis FM, Blaney SM, McCully CL, Bacher JD, Murphy RF, Poplack DG (2000) Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol 45(3):259-64\u003c/li\u003e\n\u003cli\u003eChamberlain MC (1998 Jun-Jul) Radioisotope CSF flow studies in leptomeningeal metastases. J Neuro Oncol 38(2-3):135-40\u003c/li\u003e\n\u003cli\u003eSandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH (2000 Jul) Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery 47(1):49-54\u003c/li\u003e\n\u003cli\u003eZairi F, Le Rhun E, Bertrand N, Boulanger T, Taillibert S, Aboukais R, Assaker R, Chamberlain MC (2015 Sep) Complications related to the use of an intraventricular access device for the treatment of leptomeningeal metastases from solid tumor: a single centre experience in 112 patients. J Neuro Oncol 124(2):317-23\u003c/li\u003e\n\u003cli\u003eMead PA, Safdieh JE, Nizza P, Tuma S, Sepkowitz KA (2014 Mar) Ommaya reservoir infections: a 16-year retrospective analysis. J Infect 68(3):225-30\u003c/li\u003e\n\u003cli\u003eChamberlain MC, Kormanik PA, Barba D (1997 Nov) Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 87(5):694-9\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"leptomeningeal metastasis, intrathecal chemotherapy, Ommaya reservoir, lumbar puncture, overall survival, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-9469387/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9469387/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eLeptomeningeal metastasis (LM) is a lethal complication of advanced malignancy with limited therapeutic options and poor survival. Intrathecal chemotherapy represents a standard treatment for LM and can be administered via repeated lumbar puncture (LP) or an intraventricular Ommaya reservoir. However, the comparative efficacy and safety of these two administration routes remain unclear. This study aimed to compare clinical outcomes of intrathecal chemotherapy delivered by Ommaya reservoir versus LP in patients with LM, and to provide further evidence for clarifying the advantages of Ommaya reservoir in clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eWe systematically searched MEDLINE, PubMed, and Web of Science for relevant studies published between 1986 and 2026. Studies directly comparing intrathecal chemotherapy delivered via Ommaya reservoir and LP were included in the meta-analysis. Disease control rate (DCR) was pooled as odds ratios (OR) using the Mantel–Haenszel method, and overall survival (OS) was pooled as hazard ratios (HR) using the inverse-variance method. Because adverse events (AEs) were incompletely reported in comparative studies, an additional safety analysis including single-arm cohorts was conducted using a binomial generalized linear mixed model (GLMM) with a logit link.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e A total of four comparative studies were enrolled in our meta-analysis. Three studies contributed data on DCR, and three studies contributed data on OS. The pooled analysis showed no significant difference in DCR between the Ommaya and LP groups (OR 1.43; 95% CI 0.76–2.68, \u003cem\u003ep\u003c/em\u003e = 0.27), with moderate heterogeneity (I² = 66%). In contrast, Ommaya-based intraventricular delivery was associated with significantly improved OS compared with LP (HR 0.39; 95% CI, 0.25–0.61,\u003cem\u003e p\u003c/em\u003e \u0026lt; 0.0001), with no significant heterogeneity (I² = 0%). In the additional safety analysis of six single-arm cohorts, Ommaya delivery was associated with lower estimated risks of overall AEs than LP(OR 0.43; 95% CI, 0.21–0.87, \u003cem\u003ep \u003c/em\u003e= 0.0191).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eOmmaya reservoir–based intraventricular administration of intrathecal chemotherapy may provide a survival advantage and lower risk of AEs over LP in patients with LM.\u003c/p\u003e","manuscriptTitle":"The Comparative Study of Ommaya Reservoir versus Lumbar Puncture for Intrathecal Chemotherapy in Patients with Leptomeningeal Metastasis Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 10:15:46","doi":"10.21203/rs.3.rs-9469387/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-09T13:02:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T20:33:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T08:48:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-28T18:02:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291323883549527578954249381761534216906","date":"2026-04-27T12:27:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218969902870609078796055286739030086685","date":"2026-04-24T10:47:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"157343552509585655615918866631569387857","date":"2026-04-23T20:13:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"22500914195879938999381477886441233856","date":"2026-04-22T16:24:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334386118142961116352281281029194566476","date":"2026-04-22T15:04:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169559579894926039249142160764558852384","date":"2026-04-22T10:32:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-21T10:32:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-21T10:23:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-21T10:22:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2026-04-20T08:40:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0ba28f79-0236-4f60-b8cb-3abff7ed678c","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-09T13:02:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T20:33:36+00:00","index":59,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T08:48:01+00:00","index":58,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-09T13:09:24+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 10:15:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9469387","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9469387","identity":"rs-9469387","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}