| Medical Policy |
| Subject: Convection-Enhanced Delivery of Therapeutic Agents to the Brain | |
| Document #: SURG.00099 | Publish Date: 01/06/2026 |
| Status: Reviewed | Last Review Date: 11/06/2025 |
| Description/Scope |
This document addresses the convection-enhanced delivery (CED) of therapeutic agents to the brain. CED bypasses the blood brain barrier (BBB) using catheters placed through cranial burr holes into the brain. Antineoplastics or other therapeutic agents are subsequently administered by microinfusion pump.
| Position Statement |
Investigational and Not Medically Necessary:
Convection-enhanced delivery of therapeutic agents into the brain is considered investigational and not medically necessary.
| Rationale |
Summary
Convection‑enhanced delivery of drugs has been proposed to reliably achieve intraparenchymal drug levels far above those reached in the bloodstream. Early‑phase trials have reported dose-response relationships and acceptable short‑term toxicity when used to treat both pediatric brainstem and adult hemispheric gliomas. However, the available published studies have been noncomparative, and the lone randomized trial reported negative findings. At this time, major national guidelines do not list CED as standard treatment. The clinical benefit of CED remains unproven, and further investigation in well-designed and conducted trials is needed.
Discussion
The blood‑brain barrier limits central nervous system uptake of systemically administered drugs, with less than 1 percent of circulating drug entering brain parenchyma (Lewis, 2016). Convection‑enhanced delivery uses stereotactic catheters and continuous microinfusion to generate a small positive pressure that augments diffusion with bulk flow, enabling higher local concentrations and wider intraparenchymal distribution (Barua, 2014). Distribution can extend several centimeters from the catheter tip, although realized spread depends on tissue microstructure and infusion parameters (Chaichana, 2015). Practical performance is sensitive to catheter geometry and implantation, the infusion‑rate ramp, infusate physicochemistry, and local cytoarchitecture; intraoperative and early postoperative imaging have been proposed to refine targeting and detect backflow (Barua, 2013; Chittiboina, 2015).
Across indications, most human experience with CED involves antineoplastic agents for primary brain tumors, with exploratory use in other neurologic conditions. Programs span toxin, chemotherapy, and targeted agents; imaging‑directed delivery; and device‑enabled approaches, with heterogeneous agents, endpoints, and follow‑up (Bos, 2023; Ellingson, 2021; Hall, 2006; Kunwar, 2006; Kunwar, 2007; Mueller, 2023; Pearson, 2021; Spinazzi, 2022; Thompson, 2023; van Putten, 2022).
Prospective studies have shown what the platform can achieve under controlled conditions and where the evidence remains limited. In pediatric diffuse intrinsic pontine glioma, a multicenter phase II trial of nimustine via CED reported a 1‑year survival of 60 percent from the start of radiotherapy, median overall survival (OS) of 15 months, and a 35 percent objective response rate. Serious adverse events occurred in 4 of 21 participants, including catheter‑associated hemorrhage, while 20 of 21 completed infusion as planned (Saito, 2025).
In a phase I study of 124I‑omburtamab infused by CED into the pons area of the brain, the maximum tolerated activity was 6 mCi (Souweidane, 2025). The mean lesion‑to‑whole‑body absorbed dose ratio was 816. The authors reported eleven grade‑3 central nervous system adverse events without grade‑4 or grade‑5 events, and median overall survival was 15.29 months from diagnosis with an 18.4 percent 2‑year survival rate.
Brenner (2025) reported the results of a multicenter phase 1 trial of rhenium‑186 nanoliposomes in adults with recurrent glioma delivered by CED. They stated that the treatment did not reach a maximum tolerated dose. Most adverse events were mild to moderate and median OS was 11 months overall. Tumors receiving at least 100 Gy had a median OS of 17 months compared to 6 months with less than 100 Gy, with both tumor coverage and absorbed dose correlating with survival.
Older randomized evidence remains neutral, with delivery fidelity implicated. In the PRECISE trial, postoperative CED intraparenchymal infusion of cintredekin besudotox did not improve overall survival compared to Gliadel® wafers (Arbor Pharmaceuticals, Atlanta, GA) and had more vascular adverse events; drug distribution was not verified (Kunwar, 2010).
A blinded retrospective analysis found only about half of catheters met positioning criteria and predicted limited target coverage, reinforcing the need for standardized placement and real‑time verification (Sampson, 2010). A contemporaneous review concluded that CED remained experimental because infusate delivery could not be guaranteed in practice (Lam, 2011). The 2011-2016 glioblastoma multiforme literature was predominantly preclinical, with only one clinical study, underscoring the evidentiary gap that followed early trials (Halle, 2019).
Overall, the available literature indicates that CED achieves high intratumoral exposure with negligible systemic dosing, and clinical signals track with distribution quality and absorbed dose in controlled settings. The current portfolio remains single arm and agent specific, while the one randomized trial was negative and highlighted delivery challenges. Major guidelines and federal documents for brain tumors do not recommend CED as a standard delivery method, and the approach remains investigational (National Comprehensive Cancer Network [NCCN], 2025; National Cancer Institute [NCI], 2025). The Congress of Neurological Surgeons (CNS) in 2019 noted that "other local techniques, such as convection enhanced delivery, do not appear to be under investigation for the treatment of brain metastases.”
In addition to the above, ongoing clinical trials continue to evaluate the role of CED. NCT06126744 is testing a virus called MVR-C5252, which is a modified herpes simplex virus designed to attack tumor cells. The virus is engineered to release IL-12, which stimulates the immune system, and an anti-PD-1 antibody fragment, which removes a “brake” on immune cells. The treatment is delivered directly into brain tumors through CED catheters in individuals with recurrent glioblastoma, with safety and dosing being the main goals. This trial is expected to finish in 2027. Another study, NCT04547777 is studying a combination of two agents: D2C7-IT, a toxin that targets tumor cells, and 2141-V11, an antibody that activates immune responses. These are also given through CED, and some individuals receive an implanted device called the Tumor Monorail to allow repeated sampling and follow-up infusions. This study is also focused on safety and dose finding, and it is expected to be completed in 2027.
| Background/Overview |
Throughout the body, the walls of all blood vessels are made up of endothelial cells that control passage of substances in and out of the bloodstream. There are small gaps between the cells that allow soluble chemicals to be transported in and out of various tissues via the bloodstream. However, the endothelial cells in the brain are packed very tightly, and block most chemicals and molecules from entering the brain. This property is also known as the BBB, which protects the central nervous system (CNS). The barrier can be crossed by a variety of mechanisms, including transport systems specific for amino acids or sugars, or for molecules of low molecular weight or appropriate lipid solubility. The BBB presents a challenge in the treatment of brain tumors as the majority of cancer drugs are not able to permeate the BBB, as they tend to have a polar structure or are too large in molecular weight (Zhou, 2016).
CED is a delivery technique proposed to bypass the BBB and allow the passage of specific drugs into the brain to directly treat conditions affecting the brain, such as tumors. CED uses hydraulic pressure to displace interstitial fluid with the infusate, allowing for a homogeneous distribution of small and large molecules over large distances.
| Definitions |
Antineoplastic: Having the properties of killing, or otherwise slowing the growth of, tumor cells.
Blood brain barrier (BBB): A protective mechanism that controls the passage of substances from the blood into the central nervous system.
Convection: The movement of fluids based on different characteristics between one area and another, such as a pressure gradient.
Parenchyma: The functional parts of an organ in the body.
| Coding |
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services are Investigational and Not Medically Necessary:
For the procedure codes listed below for all applications, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
| CPT |
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| 64999 |
Unlisted procedure, nervous system [when specified as stereotactic placement of infusion catheter(s) in the brain for delivery of therapeutic agent(s)] |
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| ICD-10 Procedure |
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| 00H033Z |
Insertion of infusion device into brain, percutaneous approach [when specified as catheter for convection enhanced delivery of therapeutic agent] |
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| ICD-10 Diagnosis |
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All diagnoses |
| References |
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
| Websites for Additional Information |
| Index |
Blood Brain Barrier, BBB
Blood Brain Barrier Disruption
Convection-Enhanced Delivery; CED
| Document History |
| Status |
Date |
Action |
| Reviewed |
11/06/2025 |
Medical Policy & Technology Assessment Committee (MPTAC) review. Revised Rationale, References and Websites for Additional Information sections. |
| Revised |
11/14/2024 |
MPTAC review. Revised title to add a hyphen to “convection-enhanced.” Revised Description, Rationale, Background/Overview, Definitions, References and Websites for Additional Information sections. |
| Reviewed |
11/09/2023 |
MPTAC review. Updated Rationale, References and Websites for Additional Information sections. |
| Reviewed |
11/10/2022 |
MPTAC review. Updated Rationale, References and Websites sections. |
| Reviewed |
11/11/2021 |
MPTAC review. Updated Rationale, References and Websites sections. |
| Reviewed |
11/05/2020 |
MPTAC review. Updated Rationale, References and Websites sections. |
| Reviewed |
11/07/2019 |
MPTAC review. Updated Rationale, References, and Websites sections. |
| Reviewed |
01/24/2019 |
MPTAC review. Updated Rationale, References, and Websites sections. |
| Reviewed |
02/27/2018 |
MPTAC review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background/Overview, References, and Websites sections. |
| Reviewed |
02/02/2017 |
MPTAC review. Updated Rationale, Background, References and Websites sections. |
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01/01/2017 |
Updated Coding section with 01/01/2017 CPT changes; removed code 0169T deleted 12/31/2016. |
| Reviewed |
02/04/2016 |
MPTAC review. Updated Rationale, References and Websites sections. Removed ICD-9 codes from Coding section. |
| Reviewed |
02/05/2015 |
MPTAC review. Updated Rationale, References and Websites. |
| Reviewed |
02/13/2014 |
MPTAC review. Updated Rationale, References and Websites. |
| Reviewed |
02/14/2013 |
MPTAC review. Updated Rationale, References and Websites. |
| Reviewed |
02/16/2012 |
MPTAC review. Updated Rationale, References and Websites. |
| Reviewed |
02/17/2011 |
MPTAC review. Updated Rationale, References and Websites. |
| Revised |
02/25/2010 |
MPTAC review. Title revised. Added “therapeutic agents” in place of “drugs” in the investigational and not medically necessary statement. Updated rationale, references and websites. |
| Reviewed |
02/26/2009 |
MPTAC review. Updated rationale, references and websites. |
| Reviewed |
02/21/2008 |
MPTAC review. References and web sites updated. The phrase “investigational/not medically necessary” was clarified to read “investigational and not medically necessary.” This change was approved at the November 29, 2007 MPTAC meeting. |
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10/01/2007 |
Updated Coding section with 10/01/2007 ICD-9 changes. |
| New |
03/08/2007 |
MPTAC review. Initial document development. |
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