| Medical Policy |
| Subject: Convection-Enhanced Delivery of Therapeutic Agents to the Brain | |
| Document #: SURG.00099 | Publish Date: 01/30/2025 |
| Status: Revised | Last Review Date: 11/14/2024 |
| 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 |
The BBB limits penetration of systemically administered drugs into the central nervous system. It is estimated that less than 1% of a drug administered systemically will reach the brain (Lewis, 2016).
CED involves stereotactic placement of one or more catheters through cranial burr holes directly into brain tumors or tissue. A therapeutic agent is continuously administered through the catheters by a microinfusion delivery system to create a positive pressure gradient at the catheter tip. As the pressure is maintained, it creates fluid convection or flow to supplement diffusion through the extracellular spaces and enhance the distribution of the drug to the targeted area. Other techniques for placement and differing types of intracranial catheters continue to be investigated (Barua, 2014). The goals of CED are to provide homogenous distribution of a therapeutic agent to a larger volume of brain tissue; provide higher drug concentrations directly to the tissue; and to utilize molecules that do not normally cross the BBB.
A majority of the studies on CED involve various antineoplastic agents for a variety of brain tumors (Barua, 2014; Bos, 2023; Ellingson, 2021; Hall, 2006; Kunwar, 2006, 2007, 2010; Mueller, 2023; Spinazzi, 2022; Thompson, 2023; van Putten, 2022). CED as a means of local disease control has been of particular interest in the potential treatment of malignant gliomas, which often recur within 2 centimeters of the resection cavity following tumor removal. CED can distribute chemotherapeutics up to 3 cm from the catheter tip (Chaichana, 2015). CED has also been utilized in preclinical and early clinical studies for a variety of therapeutic agents for neurodegenerative diseases (for example, progressive multifocal leukoencephalopathy [PML], Gaucher’s disease and Parkinson’s disease) as well as other neurologic conditions such as epilepsy and aromatic L-amino acid decarboxylase deficiency (Pearson, 2021).
Kunwar and colleagues (2010) reported results of a phase 3 multicenter study of 296 participants randomized to either postoperative intraparenchymal cintredekin besudotox (CB) or gliadel wafer (GW) to treat first recurrence of GBM. There was no significant difference in the primary endpoint of overall survival (OS). The median survival for CB was 9.1 months and 8.8 months for GW (p=0.476; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.67-1.18). There were no statistically significant differences between cohorts for adverse events (AE) except for a higher incidence of vascular disorders (p<0.001). The predominant vascular AE was due to the rate of pulmonary embolism in the CB group compared to the control group (8% vs. 1%, respectively; p=0.014). The actual distribution of the drug was not evaluated in this trial.
A retrospective analysis of catheter positioning and drug distribution utilizing computer software that was not available during the phase III PRECISE trial was performed by Sampson and colleagues (2010). The reviewers were blinded to the identity of the institution and the neurosurgeon responsible for catheter placement. Out of 174 participants with sufficient data, only 49.8% of the catheters placed met all criteria for positioning. The investigators also noted from simulations that the amount of target tumor tissue covered by adequately placed catheters was small. The authors concluded additional trials were necessary to determine optimized CED catheter placement; verification of drug delivery and distribution along with safety and effectiveness.
In a review by Lam (2011) it was stated “CED has remained experimental due to difficulties in guaranteeing infusate delivery.” Clinical trials continue to study the actual hardware used to deliver therapeutic agents and the accurate placement of catheters and the real-time management of high concentrations of infusate to the targeted areas. Additionally, various therapeutic agents to treat diseases affecting the brain continue to be investigated with CED as a delivery method. Three agents that have received orphan drug designation but have not received approval for manufacturing, IL13-PE38QQR and Trabedersen for malignant gliomas and IL4-Pseudomonas toxin fusion protein IL-4(38-37)-PE38KDEL for astrocytic glioma continue to be studied in clinical trials.
Halle and colleagues (2019) performed a systematic review to provide an overview of the methodological aspects used in all preclinical and clinical studies published from 2011 to 2016 where CED was used for drug delivery in the treatment of GBM. After excluding articles due to search criteria, only 30 studies focusing on CED for GBM therapy had been published during the 2011 to 2016 timeframe. Of the 30 studies, only 1 study was a clinical study and the remaining 29 studies were conducted on rodents. “This indicates that despite CED being known for over 20 years, it is still mainly used in preclinical studies.”
Investigators continue to research ways to optimize CED technology to deliver drugs to effectively treat conditions affecting the brain. Barua and colleagues (2013) noted “Effective CED depends upon a number of parameters - the diameter of the catheter, the catheter implantation method, the rate of infusion, the physicochemical characteristics of the infusate, and the cytoarchitecture of the targeted brain tissue or structure.” Preliminary studies evaluating whether techniques such as intraoperative MRI can be used to improve accuracy in the targeting and placing of the CED cannula are needed (Chittiboina, 2015). However, at this time, due to the paucity of comparative clinical trials, the safety and efficacy of the CED procedure have not been determined.
Currently, there are ongoing phase I clinical trials recruiting individuals with recurrent high-grade glioma for administration of therapeutic agents by CED. The published scientific evidence currently available is insufficient to demonstrate the safety and efficacy of administration of therapeutic agents by CED.
The National Comprehensive Cancer Network® clinical practice guideline (2024) and National Cancer Institute (2024) document for brain tumors do not address the delivery of therapeutic agents with convection-enhanced delivery.
| 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 effect 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 which bypasses the BBB 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 |
| Revised | 11/14/2024 | Medical Policy & Technology Assessment Committee (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. 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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