John Cai

Background: Glioblastoma (GBM) is the most common malignant primary brain tumor and remains universally recurrent and uniformly fatal despite surgery, chemotherapy, and radiotherapy.³ Convection‑enhanced delivery (CED) offers an alternative treatment option by infusing therapeutics directly into the tumor and peritumoral brain under positive pressure, bypassing the blood-brain barrier and avoiding systemic toxicity.^1-4 However, a systematic framework comparing different CED platforms and investigating how device design, catheter placement, and brain anatomy influence clinical performance is still lacking. This work aims to explore the major clinical and preclinical applications of CED in GBM and evaluate how logistical, technological, and anatomic factors currently limit or enable effective CED.

Methods:  A search in the PubMed database was conducted for 2021 to 2026 using the following keywords: “glioblastoma” and “convection enhanced delivery.”

Results: Early phase trials in recurrent GBM have shown that CED can safely achieve large volumes of distribution for chemotherapy, nanoliposomes, and oncolytic viruses.^1-4 Early studies of chronic pump‑based chemotherapy infusions and single‑session infusions guided by MRI show that drug distribution is highly dependent on catheter trajectory, infusion parameters, and local tissue architecture, with frequent challenges including backflow, leakage into CSF, and incomplete tumor coverage.^3-4 Trials using radiotherapeutic liposomes and oncolytic viruses suggest that higher intratumoral dose and more complete spatial coverage correlate with better survival in at least a subset of patients.¹ Overall clinical benefit remains inconsistent and is often confounded by small sample sizes, advanced disease stage, and difficulties distinguishing treatment‑related imaging change from progression.^1-4 Complementary in‑silico and computational modeling studies further demonstrate that catheter design, number of catheters, and patient‑specific anatomy can substantially alter predicted drug or dose distributions. They also show that image‑guided, model‑based optimization can reduce off‑target exposure and achieve similar coverage with fewer catheters.^5-6

Conclusion: Glioblastoma remains the most common deadly CNS tumor with no effective treatment. Further research should verify catheter number and placement optimization, evaluate chronic CED in larger cohorts, incorporate prospective image‑based distribution metrics as trial endpoints, and explore combinations of optimized CED with immunotherapies or radiopharmaceuticals to convert promising responses into consistent clinical benefit in GBM.

Works Cited:

1. Brenner, A. J., Patel, T., Bao, A., Phillips, W. T., Michalek, J. E., Youssef, M., Weinberg, J. S., Matsuoka, C. K., Hedrick, M. H., LaFrance, N., Moore, M., & Floyd, J. R. (2025). Convection enhanced delivery of Rhenium (186Re) Obisbemeda (186RNL) in recurrent glioma: a multicenter, single arm, phase 1 clinical trial. Nature Communications, 16(1), 2079. https://doi.org/10.1038/s41467-025-57263-1

2. Narsinh, K. H., Kumar, K., Bankiewicz, K., Martin, A. J., Berger, M., Clarke, J., Taylor, J., Bush, N. a. O., Molinaro, A. M., Aghi, M., & Butowski, N. (2025). A phase I study of convection-enhanced delivery (CED) of liposomal-irinotecan using real-time magnetic resonance imaging in patients with recurrent high-grade glioma. Journal of Neuro-Oncology, 172(1), 219–227. https://doi.org/10.1007/s11060-024-04904-y

3. Spinazzi, E. F., Argenziano, M. G., Upadhyayula, P. S., Banu, M. A., Neira, J. A., Higgins, D. M. O., Wu, P. B., Pereira, B., Mahajan, A., Humala, N., Al-Dalahmah, O., Zhao, W., Save, A. V., Gill, B. J. A., Boyett, D. M., Marie, T., Furnari, J. L., Sudhakar, T. D., Stopka, S. A., . . . Bruce, J. N. (2022). Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial. The Lancet Oncology, 23(11), 1409–1418. https://doi.org/10.1016/s1470-2045(22)00599-x

4. Van Putten, E. H., Kleijn, A., Van Beusechem, V. W., Noske, D., Lamers, C. H., De Goede, A. L., Idema, S., Hoefnagel, D., Kloezeman, J. J., Fueyo, J., Lang, F. F., Teunissen, C. E., Vernhout, R. M., Bakker, C., Gerritsen, W., Curiel, D. T., Vulto, A., Lamfers, M. L., & Dirven, C. M. (2022). Convection Enhanced Delivery of the Oncolytic Adenovirus Delta24-RGD in Patients with Recurrent GBM: A Phase I Clinical Trial Including Correlative Studies. Clinical Cancer Research, 28(8), 1572–1585. https://doi.org/10.1158/1078-0432.ccr-21-3324

5. Wang, Y., Zhang, A., Cao, L., Lou, Z., Si, X., Zhang, X., Wang, W., & Zhu, J. (2025). Evaluation of drug distributions in brain tumor therapy: An in silico comparative study of multi-side-hole and standard end-hole catheters in convection-enhanced delivery. International Journal of Pharmaceutics, 685, 126230. https://doi.org/10.1016/j.ijpharm.2025.126230

6. Wu, C., Hormuth, D. A., Christenson, C. D., Woodall, R. T., Abdelmalik, M. R., Phillips, W. T., Hughes, T. J., Brenner, A. J., & Yankeelov, T. E. (2024). Image-guided patient-specific optimization of catheter placement for convection-enhanced nanoparticle delivery in recurrent glioblastoma. Computers in Biology and Medicine, 179, 108889. https://doi.org/10.1016/j.compbiomed.2024.108889