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  • Intraarterial Chemotherapy for Glioblastoma: Where We Are Now and Where We Are Going?

    Final Number:

    Shamik Chakraborty MD; Julia Rachel Schneider BS; Alexis Demopoulos MD; David J. Langer MD; Rafael Alexander Ortiz MD; John A. Boockvar MD

    Study Design:
    Clinical Trial

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2017 Annual Meeting

    Introduction: Intraarterial chemotherapy with blood/brain barrier (BBB) disruption may allow for increased efficacy of treatment for malignant glioma. We present a summary of our clinical trials using this treatment paradigm and highlight our future directions.

    Methods: Phase I/II clinical trials were conducted between 2009-2017 to evaluate the safety and efficacy of selective intraarterial infusion (SIACI) of mannitol for osmotic BBB disruption and infusion of either bevacizumab, cetuximab, or temozolomide into the arterial distribution of high grade gliomas.

    Results: A trial using SIACI of bevacizumab after osmotic BBB disruption in 30 patients with recurrent glioblastoma found that it was safe and well tolerated, and could reduce tumor volume. A second trial of 14 GBM patients showed a PFS of 10 months with a single dose of IA bevacizumab. A follow up trial with 16 patients showed that a single dose of SIACI of bevacizumab had a progression-free durability of 4 months. SIACI of cetuximab and temozolomide for glioblastoma were shown to be safe and well tolerated in completed phase-I trials, with temozolomide offering a median survival of 2 years. A trial of 12 pediatric patients with diffuse intrinsic pontine glioma (DIPG) also showed that SIACI of cetuximab and bevacizumab was well-tolerated and offered symptom relief. A subgroup analysis of 65 glioblastoma patients who received SIACI of bevacizumab showed that MRI imaging could be used to predict survival.

    Conclusions: Intraarterial chemotherapy for focal glioblastoma treatment is a promising treatment modality that could improve tumor control and limit systemic toxicity. Over 125 patients have been treated with BBB disruption followed by SIACI of chemotherapy with good safety and results suggesting improved efficacy. Phase II trials are underway to better evaluate efficacy, and as newer BBB disruption techniques such as laser interstial thermal therapy (LITT) or focused ultrasound are developed, this may improve survival for glioblastoma patients.

    Patient Care: This treatment modality could offer a way to improve survival in patients with malignant glioma, with potentially fewer systemic side effects compared to standard chemotherapy. There may also be future cost benefits with intra-arterial chemotherapy.

    Learning Objectives: Following this presentation, viewers will better understand the treatment modality of intraarterial chemotherapy, the potential survival benefits, its low side effect profile, and techniques by which to focally target the arterial distribution of the tumor. Future directions of intraarterial chemotherapy trials will be discussed, as will be the use of new modalities being developed to disrupt the blood/brain barrier such as LITT, focused ultrasound, and nanoparticles etc.

    References: 1. Riina HA, Knopman J, Greenfield JP, Fralin S, Gobin YP, Tsiouris AJ, Souweidane MM, Boockvar JA (2010) Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note. Interv Neuroradiol 16:71–76 2. Chakraborty S, Filippi CG, Burkhardt J-K, Fralin S, Ray A, Wong T, Ortiz R, Langer DJ, Boockvar JA (2016) Durability of single dose intra-arterial bevacizumab after blood/brain barrier disruption for recurrent glioblastoma. J Exp Ther Oncol 11:261–267 3. Shin BJ, Burkhardt J-K, Riina HA, Boockvar JA (2012) Superselective intra-arterial cerebral infusion of novel agents after blood-brain disruption for the treatment of recurrent glioblastoma multiforme: a technical case series. Neurosurg Clin N Am 23:323–9, ix–x 4. Chakraborty S, Filippi CG, Wong T, et al (2016) Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study. J Neurooncol 128:405–415 5. Boockvar JA, Tsiouris AJ, Hofstetter CP, et al (2011) Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article. J Neurosurg 114:624–632 6. Burkhardt J-K, Shin BJ, Schlaff CD, Riina H, Boockvar JA (2011) Cost analysis of intra-arterial versus intra-venous delivery of bevacizumab for the treatment of recurrent glioblastoma multiforme. J Exp Ther Oncol 9:183–186 7. Burkhardt J-K, Riina H, Shin BJ, Christos P, Kesavabhotla K, Hofstetter CP, Tsiouris AJ, Boockvar JA (2012) Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival. World Neurosurg 77:130–134 8. Burkhardt J-K, Hofstetter CP, Santillan A, Shin BJ, Foley CP, Ballon DJ, Pierre Gobin Y, Boockvar JA (2012) Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench. J Clin Neurosci 19:1568–1572 9. Burkhardt J-K, Riina HA, Shin BJ, Moliterno JA, Hofstetter CP, Boockvar JA (2011) Intra-Arterial Chemotherapy for Malignant gliomas: a critical analysis. Interv Neuroradiol 17:286–295 10. Riina HA, Fraser JF, Fralin S, Knopman J, Scheff RJ, Boockvar JA (2009) Superselective intraarterial cerebral infusion of bevacizumab: a revival of interventional neuro-oncology for malignant glioma. J Exp Ther Oncol 145–150

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