Pending Policies - Surgery
Direct Brain Infusion - Convection-Enhanced Delivery of Therapeutic Agents
This medical policy has become inactive as of the end date above. There is no current active version and is not to be used for current claims adjudication or business purposes.
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Interstitial infusion of therapeutic agents directly into the brain through an infusion catheter (e.g., convection-enhanced delivery) is considered experimental, investigational and/or unproven.
Treatment of central nervous system (CNS) diseases can be difficult because the blood brain barrier (BBB) limits or blocks delivery of drug molecules to the brain. Therefore, direct delivery of therapeutics to the brain is an active area of investigation. One of these techniques, convection-enhanced delivery (CED), involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered using continuous low-positive-pressure bulk flow. (1) This technique has been proposed for treatment of brain tumors, Parkinson disease, epilepsy and other brain disorders.
No randomized controlled trials have established superiority of blood brain barrier disruption (BBBD) techniques over the use of chemotherapy. Although these techniques have been used for over twenty years, their efficacy has not been established. Chemotherapy with BBBD has been associated with a higher risk of complications that include seizures, focal neurologic deficits, obtundation, cerebral herniation, stroke and death. These complications are then multiplied by the side-effects related to the chemotherapy itself.
A search of the literature was completed through MEDLINE database through November 2008. There is limited scientific data to permit conclusions regarding the use of direct brain infusion catheter(s) in the brain for delivery of therapeutic agent(s), and for the treatment of brain tumors, Parkinson disease, epilepsy or other disorders of the brain. Although the ongoing clinical trial data is promising, further study is needed to demonstrate whether the use of this therapy leads to improved outcomes.
A search of peer reviewed literature was performed through November 2011. The following is a summary of the key literature to date.
Bruce, J.N., et al. carried out a prospective, dose-escalation phase 1b study to assess the safety profile of convection-enhanced delivery of the chemotherapeutic agent, topotecan, for the management of recurrent malignant gliomas, as well as evaluate radiographic response and survival. (15) The reported results indicated “Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated.” The study established the maximum tolerated dose for future phase II studies. “The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials” was noted by the authors.
Although the study is promising, further studies are needed. This update failed to identify any additional information that would change the coverage position of this medical policy.
A search of peer reviewed literature was conducted through June 2014; the search revealed several case studies (16, 17), small studies (18, 19) and one moderate sized study of less than 150 participants (20). Finding no large studies with long term results, the coverage statement remains unchanged.
A search of peer reviewed literature conducted through April 18, 2016 identified no new clinical trial publications or any significant scientific information that would change the coverage position of this medical policy.
National Comprehensive Cancer Network
No mention of convection enhanced delivery of therapeutic agents was identified in the National Comprehensive Cancer Network (NCCN) V1.2015 Guidelines for Central Nervous System Cancers. (21)
In January 2017, Jahangiri et al. performed a comprehensive review of eighty-seven articles including preclinical studies and the most prominent clinical trials of convection-enhanced delivery (CED) in the treatment of glioblastoma. (22) Although CED holds considerable promise in neurological drug delivery, clinical trials have had limited success. Reasons identified for these failures include:
• Choice of agent- The choice of agent to be delivered is exceedingly important in the success of CED. The inclination to use particularly toxic agents based on the presumption that local delivery ensures the agent only gets to the tumor must be avoided. This is because of the need to target not just the tumor but also the infiltrating tumor cells within the peritumoral white matter, which also contains normal brain cells. Therefore, the delivered agent must possess a wide therapeutic index.
• Cannula design- Cannulas were designed with multiple catheters at their tips, which would have lowered infusion rates at each opening. Unfortunately, they were not effective, since most of the infusate was distributed via the proximal tip.
• Cannula placement- Retrospective analysis of prior trials have suggested that many patients had optimal cannula positioning, which could explain the lack of survival benefit.
• Intratumoral penetration- Several physiological and physical barriers prevent full tumor distribution. One physiological barrier is that certain tumor zones metabolize agents faster than others, while a physical barrier can be the aberrant blood vessel growth and increased intercapillary spaces that create differential rates of clearance of agents.
• Reflux- A major concern with CED is infusate reflux. Reflux occurs when the pressure gradient between the cannula and the tumor region equalizes, resulting in the loss of drug flow into the target mass.
• Tracking infusate delivery- Most of the early trials did not assess the efficacy of delivery.
• Cost of procedure- CED, which includes time in the operating room and/or magnetic resonance imaging, cannulas and the platforms needed to place them, infusates, time of staff performing the procedure, and associated inpatient stays, is quite costly.
• Postprocedural imaging- The optimal endpoint for CED is unclear. Short-term imaging response may be needed as a response metric alongside conventional parameters such as progression-free survival or overall survival.
These technical shortcomings must be addressed in order to allow CED to fulfill its therapeutic potential. Overall, CED holds promise for treating glioblastoma and warrants further preclinical and clinical development.
Zhou et al. (2017) reviewed the application of CED in diffuse intrinsic pontine glioma (DIPG). (23) Although the physical parameters influencing drug distribution in CED have not been thoroughly clarified, the ability of CED to achieve high concentrations of a therapeutic agent over large volumes of brain tissue has led to several clinical trials in patients with neurodegenerative disorders and malignant gliomas. CED of antineoplastic agents has shown considerable promise in phase I and phase II clinical trials in patients with recurrent malignant gliomas. However, phase III results are less encouraging. CED in the treatment of DIPG has produced encouraging results in preclinical studies. Future advances in CED for DIPG treatment will need to focus on two fronts: the selection or development of therapeutic agents for delivery via CED, and the improvement of the technique of CED.
National Comprehensive Cancer Network
No mention of convection enhanced delivery of therapeutic agents was identified in the NCCN V1.2017 Guidelines for Central Nervous System Cancers. (24)
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None [Deleted 1/2017: 0169T]
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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does have a National Coverage Determination (NCD) that states that the use of osmotic blood brain barrier disruption is not reasonable and necessary when it is used as a part of a treatment regimen for brain tumors. (2)
A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. Vogelbaum MA, Aghi MK. Convection-enhanced delivery for the treatment of flioblastoma. Neuro Oncol. 2015 Mar; 17 Suppl 2:ii3-ii8. PMID 25746090
2. Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for Blood Brain Barrier Osmotic Disruption for Treatment of Brain Tumors (110.20). March 20, 2007. Available at <http://www.cms.gov> (accessed March 12, 2018).
3. Broaddus WC, Prabhu SS, Gillies GT, et al. Distribution and stability of antisense phosphorothioate oligonucleotides in rodent brain following direct intraparenchymal controlled-rate infusion. J Neurosurg. 1998 Apr; 88(4):734-42. PMID 9525721
4. Prabhu SS, Broaddus WC, Gillies GT, et al. Distribution of macromolecular dyes in brain using positive pressure infusion: a model for direct controlled delivery of therapeutic agents. Surg Neurol. 1998 Oct; 50(4):367-75; discussion 375. PMID 9817462
5. Morrison PF, Chen MY, Chadwick RS, et al. Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics. Am J Physiol. 1999 Oct; 277(4 Pt 2):R1218-29. PMID 10516265
6. Haar PJ, Stewart JE, Gillies GT, et al. Quantitative three-dimensional analysis and diffusion modeling of oligonucleotide concentrations after direct intra parenchymal brain infusion. IEEE Trans Biomed Eng. 2001 May; 48(5):560-9. PMID 11341530
7. Gill SS, Patel NK, Hotton GR, et al. Direct Brain infusion of glial cell-line derived neurotrophic factor in Parkinson disease. Nat Med. 2003 May; 9(5):589-95. PMID 12669033
8. Gillies GT, Smith JH, Humphrey JA, et al. Positive pressure infusion of therapeutic agents into brain tissues: mathematical and experimental simulations. TechnolHealth Care. 2005; 13(4):235-43. PMID 16055972
9. Gill SS, Patel NK, Hotton GR, et al. Addendum: Direct Brain infusion of glial cell-line derived neurotrophic factor in Parkinson disease. Nat Med. 2006 Apr; 12(4):479.
10. Kim JJ, Mareci TH, Sarntinoranont M. Voxelized model of interstitial transport in nervous tissue following direct infusion into white matter. Conf Proc IEEE Eng Biol Soc. 2007; 2007:2114-7. PMID 18002405
11. Weingart J, Grossman SA, Carson KA, et al. Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous 06-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial. J Clin Oncol. 2007 Feb 1; 25(4):399-404. PMID 17264335
12. Centers for Medicare and Medicaid Services (CMS). Decision Memo for Blood Brain Barrier Disruption (BBBD) Chemotherapy (CAG-00333N). Medicare Coverage Database. Baltimore, MD: CMS; (2007 Mar 20). Available at <https://www.cms.hhs.gov> (accessed April 18, 2016).
13. Sampson JH, Raghavan R, Provenzale JM, et al. Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin. AJR Am J Roentgenol. 2007 Mar; 188(3):703-9. PMID 17312057
14. Rogawski MA. Convection-enhanced delivery in the treatment of epilepsy. Neurotherapeutics. 2009 Apr; 6(2):344-351. PMID 19332329
15. Bruce JN, Fine RL, Canoll P, et al. Regression of recurrent malignant gliomas with convection-enhanced delivery topotecan. Neurosurgery. 2011 Dec; 69(6):1272-80. PMID 21562434
16. Barua NU, Lowis SP, Woolley M, et al. Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma. Acta Neurochir (Wien). 2013 Aug; 155(8):1459-65. PMID 23595829
17. Anderson RC, Kennedy B, Yanes CL, et al. Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr. 2013 Mar; 11(3):289-95. PMID 23240851
18. Mueller S, Polley MY, Lee B, et al. Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study. J Neurooncol. 2011 Jan; 101(2):267-77. PMID 20563833
19. White E, Bienemann A, Taylor H, et al. A phase 1 trial of carboplatin administered by convection-enhanced delivery to patients with recurrent/progressive glioblastoma multiforme. Contemp Clin Trials. 2012 Mar; 33(2):320-31. PMID 22101221
20. Bogdahn U, Hau P, Stockhammer G, et al. Targeted therapy for high-grade glioma and the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 2011 Jan; 13(1):132-42. PMID 20980335
21. National Comprehensive Cancer Network Guidelines Version 1.2015 Central Nervous System Cancers. Available at <http://www.nccn.org> (accessed April 18, 2016).
22. Jahangiri A, Chin A, Flanigan, P, et al. Convectoin-enhanced delivery in glioblastoma : a review of preclinical and clinical studies. J Neurosurg. 2017 Jan; 126(1):191-200. PMID 27035164
23. Zhou Z, Singh R, Souweidane MM. Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment. Curr Neuropharmacol. 2017; 15(1):116-128. PMID 27306036
24. National Comprehensive Cancer Network Guidelines Version 1.2017 Central Nervous System Cancers. Available at <http://www.nccn.org> (accessed March 12, 2018).
|4/30/2020||Document became inactive.|
|4/15/2018||Document updated with literature review. Coverage unchanged. References 1-2, 22-24 added.|
|4/15/2017||Reviewed. No changes.|
|6/15/2016||Document updated with literature review. Coverage unchanged.|
|10/15/2015||Reviewed. No changes.|
|8/1/2014||Document updated with literature review. Coverage clarified to include an example of a type of infusion-convection-enhanced delivery. Title changed to Direct Brain Infusion - Convection-Enhanced Delivery of Therapeutic Agents.|
|2/15/2012||Document updated with literature review. Coverage unchanged.|
|2/15/2009||Revised/updated entire document|
|1/1/2007||New medical document|
|Title:||Effective Date:||End Date:|
|Direct Brain Infusion - Convection-Enhanced Delivery of Therapeutic Agents||04-15-2017||04-14-2018|
|Direct Brain Infusion - Convection-Enhanced Delivery of Therapeutic Agents||06-15-2016||04-14-2017|
|Direct Brain Infusion - Convection-Enhanced Delivery of Therapeutic Agents||10-15-2015||06-14-2016|
|Direct Brain Infusion - Convection-Enhanced Delivery of Therapeutic Agents||08-01-2014||10-14-2015|
|Direct Brain Infusion of Therapeutic Agents||02-15-2012||07-31-2014|
|Direct Brain Infusion of Therapeutic Agents||02-15-2009||02-14-2012|
|Direct Brain Infusion of Therapeutic Agents||01-01-2007||02-14-2009|