Convection–enhanced delivery (CED) is a delivery technique to bypass the blood brain barrier (BBB) and administer therapeutic agents directly into targeted brain parenchyma or tissue. CED involves one or more catheters stereotactically placed through cranial burr holes into the brain. Antineoplastics or other therapeutic agents are subsequently administered by microinfusion pump. This document addresses the CED process for administering antineoplastics and other agents into the brain and the surrounding tissue.

Investigational and Not Medically Necessary:

Convection-enhanced delivery of therapeutic agents into the brain is considered investigational and not medically necessary.

Convection-enhanced delivery (CED) is a highly technical process that involves stereotactic placement of one or more catheters through cranial burr holes directly into brain tumors or tissue. A therapeutic agent is 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 and enhance the distribution of the drug to the targeted area. 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 blood brain barrier (BBB).

Standard methods of delivering drugs to the brain by intravenous infusions of systemic drugs resulted in limited penetration of the central nervous system. Intraventricular and intratumoral injections were limited as the molecular weight and solubility of the agent impacted the diffusion. As a result, innovative therapies continue to be investigated.

A majority of the studies on CED involve various antineoplastic agents for a variety of brain tumors (Hall, 2006; Kunwar, 2006, 2007; 2010). CED has also been utilized in preclinical and early clinical studies for a variety of therapeutic agents for neurodegenerative diseases (e.g., progressive multifocal leukoencephalopathy (PML), Gaucher's disease and Parkinson's disease) as well as other neurologic conditions such as epilepsy.

Hall and Sherr (2006) noted an ongoing study using brain phantom gel to determine the best drug delivery system design and a reliable method to test the system. The use of magnetic resonance imaging and other techniques are also being studied to determine effective and accurate real-time assessments of the convective process (Hall, 2006). Clinical trials and small case series continue to evaluate the appropriate placement of catheters, volume and the specific drug and concentration of drug infused (Kunwar, 2007; Sampson, 2007; Sampson, 2008; Tanner, 2007). However, the studies have not been conclusive.

Kunwar and colleagues (2006) reported an investigational trial of 53 individuals with malignant gliomas; of which 47 were glioblastoma multiforme (GBM). Fifty-one participants received CED infused cintredekin besudotox (IL13-PE38QQR) as a single infusion after resection or sequentially by intratumoral treatment followed by resection and subsequent intraparenchymal infusion. Adverse events were reported in all 3 phases (pre-CED; peri-CED; post-CED), which sometimes were related to placement of the catheters and sometimes were related to the instillation of cintredekin besudotox. Side effects included headaches, sensory disturbances and hemiparesis.

In a 2009 review, Bidros noted the increased pressure gradient within a tumor versus the normal brain along with the heterogeneity of drug distribution within the tumor itself are potential "limiting factors in drug delivery by this method."

Kunwar and colleagues (2010) reported results of a phase III multicenter study of 296 participants randomized to either postoperative intraparenchymal cintredekin besudotox (CB) or gliadel wafer (GW) to treat first recurrence of glioblastoma multiforme (GBM). There was no significant difference in the primary endpoint of overall survival. The median survival for CB was 9.1 months and 8.8 months for GW (P= 0.476; hazard ratio 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 (Sampson, 2010).

Clinical trials continue to study alternative therapeutic agents along with imaging techniques to investigate CED as a method to provide therapies for brain tumors and other diseases affecting the brain. Two agents that have received orphan drug designation but have not received approval for manufacturing, IL13-PE38QQR for malignant gliomas, and IL4-Pseudomonas toxin fusion protein IL-4(38-37)-PE38KDEL for astrocytic glioma continue to be studied in clinical trials.

Due to the paucity of comparative clinical trials of CED versus standard therapeutic methods, the safety and efficacy of the convection-enhanced delivery procedure has not been determined.

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 blood brain barrier (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.

CED is a novel delivery technique for treating brain tumors. Usually two weeks following tumor resection and when the individual is stable, one or more catheters are stereotactically placed into the brain parenchyma. In order to achieve homogenous distribution of the drug into cells infiltrated by tumor, the catheters cannot be placed in any previously resected cavity. After administering the antineoplastic for 96 hours or more, the catheters are removed, and the individual is discharged from the hospital (Kunwar, 2006).

According to the American Cancer Society, approximately 22,020 American adults will be diagnosed with malignant brain or spinal cord tumors in 2010, and approximately 13,140 will die from malignant tumors. Brain and spinal cord tumors account for 21% of childhood cancers and are the second most common cancer in children.

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 pressure.

Parenchyma: The functional parts of an organ in the body.

Stereotactic: A method used in neurosurgery and research for locating points within the brain utilizing an external,  three-dimensional frame of reference usually based on a 3-dimensional coordinate system.

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.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Bidros DS, Vogelbaum MA. Novel drug delivery strategies in neuro-oncology. Neurotherapeutics. 2009; 6:539-546.
2. Hall WA, Rustamzadeh E, Asher AL. Convection-enhanced delivery in clinical trials. Neurosurg Focus. 2003; 14(2):e2.
3. Hall WA, Sherr GT. Convection-enhanced delivery: targeted toxin treatment of malignant glioma. Neurosurg Focus. 2006; 20(4):E10.
4. Kunwar S, Chang SM, Prados MD, et al. Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. Neurosurg Focus. 2006; 20(4):E15.
5. Kunwar S, Chang S, Westphal M, et al.; PRECISE Study Group. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. J Neurosurg. 2010; 113(2):301-309.
6. Kunwar S, Prados MD, Chang SM, et al.; Cintredekin Besudotox Intraparenchymal Study Group.  Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol. 2007; 25(7):837-844.
7. Lonser RR, Oldfield EH. Beyond the blood-nervous system barrier: Convection-enhanced delivery targets CNS disorders. American Association of Neurological Surgeons (AANS) Bulletin. 2004; 13(4). Available at: http://www.aans.org/Publications%20and%20Journals/AANS%20Neurosurgeon/AANS%20Neurosurgeon%20Issues/2004/Winter%202004%20-%20Issue%204/Beyond%20the%20Blood-Nervous%20System%20Barrier%20-%20Convection-Enhanced%20Delivery%20Targets%20CNS%20Disorders.aspx?sc_database=web. Accessed on January 3, 2011.
8. Lonser RR, Schiffman R, Robison RA, et al. Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology. 2007; 68(4):254-261.
9. Muro K, Das S, Raizer JJ. Convection-enhanced and local delivery of targeted cytotoxins in the treatment of malignant gliomas. Technol Cancer Res Treat. 2006; 5(3):201-213.
10. Patel SJ, Shapiro WR, Laske DW, et al. Safety and feasibility of convection-enhanced Cotara for the treatment of malignant glioma: initial experience in 51 patients. Neurosurgery. 2005; 5(6):1243-1253.
11. Sampson JH, Akabani G, Archer GE, et al. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro Oncol. 2008; 10(3):320-329.
12. Sampson JH, Archer G, Pedain C, et al.; PRECISE Trial Investigators. Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg. 2010; 113(2):301-319.
13. Sampson JH, Brady ML, Petry NA, et al. Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning. Neurosurgery. 2007; 60(2 Suppl 1):ONS89-ONS98.
14. Slevin JT, Gash DM, Smith CD, et al. Unilateral intraputaminal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal. Neurosurg Focus. 2006; 20(5):E1.

Government Agency, Medical Society, and Other Authoritative Publications:

1. National Comprehensive Cancer Network^® (NCCN). Clinical Practice Guidelines in Oncology™: Central Nervous System Cancers (V.1.2011). October 13, 2010 © 2010 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org/index.asp. Accessed on December 16, 2010.

1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on December 16, 2010.
2. National Cancer Institute (NCI) – Adult Brain Tumors Treatment PDQ^®. Last modified July 8, 2010. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adultbrain/healthprofessional. Accessed on December 16, 2010. 

Blood Brain Barrier, BBB
Blood Brain Barrier Disruption
Convection Enhanced Delivery; CED