Retrospective Review of Intra-Cerebrospinal Fluid (CSF) Drug Delivery in CNS Malignancies: Safety, Clinical Efficacy and Pharmacokinetic Profiles of Intracerebroventricular (ICV), Lumbar Intrathecal (LIT), and Intra-Cisterna Magna (ICM) Injections.

Background/

Objectives

The blood-brain barrier and blood-CSF barrier limit the uptake of CNS-targeted therapeutics, warranting utilization of intra-cerebrospinal fluid (CSF) drug delivery. Here we review and compare the safety and distribution of different intra-CSF delivery methods reported in clinical literature.

Methods

A retrospective literature review of three common CSF access methods was performed. A search consisting of clinical trials published on PubMed from 2000-2024 using the following search terms-intracerebroventricular/intraventricular/ICV, intrathecal/IT, intralumbar/lumbar puncture, cisterna magna/ICM/IT-CM, drug delivery, drug administration, and CSF-yielded 38 intracerebroventricular (ICV), 110 lumbar intrathecal (LIT), and six intra-cisterna magna (ICM) studies.

Results

After final exclusion criteria were applied, there were 12 ICV, two LIT, and zero ICM publications remaining for analysis. ICV-specific safety was addressed in 11 ICV publications, with headache, nausea, and vomiting being among the most frequently mentioned procedure-associated adverse events (AEs). LIT-specific safety was provided in only one of the two studies, reporting mostly grade 1/2 AEs but also an instance of grade 4 myelosuppression. For clinical efficacy, progression-free survival (PFS), overall survival (OS), and disease progression rates were largely variable across studies. Pharmacokinetics were analyzed in four ICV studies.

Conclusions

The safety profiles of both ICV and LIT injections are acceptable, showing mostly mild to moderate procedure-associated AEs and less common treatment-related AEs than systemically administered therapies. Additionally, ICV achieves therapeutic goals more consistently than the other intra-CSF delivery methods. To date, there are insufficient data to show dose-related response with intra-CSF delivery. Novel tools are being developed to improve upon intra-CSF delivery that will ideally lead to improved patient outcomes in the near future.