Endovascular therapies for malignant gliomas: Challenges and the future

Journal of Clinical Neuroscience xxx (2016) xxx–xxx

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Review

Endovascular therapies for malignant gliomas: Challenges and the future YouRong Sophie Su a,1, Rohaid Ali a,1, Abdullah H. Feroze a, Gordon Li a, Michael T. Lawton b, Omar Choudhri b,⇑ a b

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Avenue, Room M779, San Francisco, CA 94143-0112, USA

a r t i c l e

i n f o

Article history: Received 14 October 2015 Accepted 25 October 2015 Available online xxxx Keywords: Anaplastic glioma Blood-brain barrier Endovascular GBM Glioblastoma Malignant gliomas

a b s t r a c t Malignant gliomas are very difficult tumors to treat, with few effective therapies, early progression and high rates of recurrence. Here we review the literature on malignant gliomas treated with endovascular therapy. Endovascular therapy for malignant gliomas falls into one of three categories: (1) neoadjuvant embolization and devascularization; (2) direct intra-arterial drug delivery; and (3) disruption of the blood–brain barrier for improved intra-arterial drug delivery. There is a range of therapeutic benefits based on the endovascular intervention used. Challenges remain for those who aim to treat malignant gliomas with an endovascular approach. Specifically, embolization is difficult to accomplish in the small vessels that feed into malignant gliomas, and intra-arterial chemotherapy has yet to prove itself better than traditional intravenous chemotherapy. However, there exists promise in the therapeutic potential of intra-arterial chemotherapy paired with disruption of the blood–brain barrier at tumor-specific sites, and as such, continued research to optimize this approach is expected to yield benefit for patients with malignant gliomas. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Malignant gliomas represent World Health Organization (WHO) grades III and IV gliomas, which are a pathologically heterogeneous collection of glial-derived tumors of the central nervous system. Grade III gliomas include anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas, and anaplastic ependymomas; glioblastoma multiforme (GBM) is the only WHO grade IV glioma. Taken together, malignant gliomas – otherwise known as high-grade gliomas – carry an annual incidence of five cases per 100,000 population, resulting in 14,000 new cases per year in the USA [1] and 74,000 new cases worldwide [2,3]. The traditional therapeutic regimen for malignant gliomas is multimodal, involving a combination of surgical resection, chemotherapy, and radiation. However, despite decades of work attempting to improve this regimen, the prognosis for malignant gliomas remains poor. Median survival for patients with grade III gliomas is 36–41 months and for patients with GBM is 12–15 months [4,5]. The 5 year survival for patients with malignant gliomas is a mere 6.1% [6].

⇑ Corresponding author. Tel.: +1 610 202 7144. 1

E-mail address: [email protected] (O. Choudhri). These authors have contributed equally to the manuscript.

To improve long-term survival for patients with malignant gliomas, an endovascular approach to therapy is an increasingly appealing option; see Table 1 for a summary of current trials using an endovascular approach for gliomas. Previously, antineoplastic endovascular approaches have been used successfully for pathologies including retinoblastoma and hepatocellular carcinoma [7,8]. Such approaches are attractive for intracranial use, as access to a single vascular supply can provide access to a large surface area. Moreover, recent advances in catheter technology allow endovascular therapy with minimal manipulation of the brain, a high concentration of drugs or therapeutic agents in the tumor, and reduced systemic and cerebral toxicities, thus offering a well tolerated technique overall, even in instances where multiple interventions might be required. Here, we detail our review of the latest advances in endovascular therapy for malignant gliomas, including challenges, approaches, and future possibilities. 2. Endovascular approaches to treating glioma Broadly, modern endovascular therapy for malignant gliomas can be divided into three major categories: (1) neoadjuvant embolization and devascularization; (2) direct intra-arterial (IA) drug delivery; and (3) disruption of the blood–brain barrier (BBB) for improved IA drug delivery. Each of these techniques has been theorized and utilized for decades with mixed results, however

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Please cite this article in press as: Su YS et al. Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci (2016), http://dx. doi.org/10.1016/j.jocn.2015.10.019

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Condition

Treatment

Type of study

Patients

Outcomes

Comments

Author

Grade III anaplastic astrocytoma studies

Neoadjuvant cisplatin/ etoposide + RT vs concurrent chemoradiation

Prospective, nonrandomized

20

MS = 45 mo vs 12 mo

Chemotherapy delivered either intracarotid or intravertebral; most common SE was nausea/ vomiting

Madajewicz et al. [55]

IA vs IV BCNU +/- IV 5FU

Randomized phase III

112

At 2 y, survival rate of 60% (IV) vs 25% (IA) for pts receiving BCNU; 5FU did not increase survival

IA BCNU had severe toxicities of encephalopathy and ocular toxicity so early termination of trmt

Shapiro et al. [17]

IA CP and IV etoposide

Phase II

10

MS = 26 wk

200 mg/m2/d IA CP and 100 mg/m2/d IV etoposide  2 d q 4 wk; most common SE were thrombocytopenia and leukopenia

Newton et al. [56]

IA ACNU

Prospective, phase II

35

MS = 14.2 mo

1st 100 mg ACNU dose given postop, prior to RT. 7 more ACNU doses given post-RT (max 700 mg total); rare systemic complications, but 2 patients had retinal toxicities

Roosen et al. [57]

IA vs IV ACNU

Randomized, phase III

43 (17 IA vs 16 IV)

MS = 17 mo (IA) vs 20 mo (IV); median PFS = 6 mo (IA) vs 4 mo (IV); no significant difference in either outcome

80–90 mg/m2 ACNU q5–6 wk; no significant systemic toxicity between IA and IV, but 1 pt in IA group had hemiparesis

Imbesi et al. [21]

RT with concomitant vs sequential IA cisplatin

Randomized, phase II

23 (12 concomitant vs 11 sequential)

MS = 10.8 mo (concomitant) vs 9.6 mos (sequential)

Fixed dose of 150 mg cisplatin (unless creatinine clearance was reduced)

Mortimer et al. [58]

Neoadjuvant cisplatin/ etoposide + RT vs concurrent chemoradiation

Prospective, nonrandomized

63

MS = 20 mo vs 7 mo

Chemotherapy delivered either intra-carotid or intravertebral

Madajewicz et al. [55]

IA vs IV BCNU +/- IV 5FU

Randomized phase III

336

Similar survival rates at 2 y between 2 trmt types; 5FU did not increase survival

IA BCNU had severe toxicities of encephalopathy and ocular toxicity so early termination of trmt

Shapiro et al. [17]

IA BCNU pre-RT

Phase II

28

MS = 37 wk for all 28 pts; 56 wk for 19 pts who completed at least 3 doses

400 mg dose q 4 wk  4 doses; fatal leukoencephalopathy in 2 pts prevented phase III trial

Bashir et al. [59]

Prior RT with infra- or supra-ophthalmic infusion

Prospective, nonrandomized

43 (25 infraophthalmic vs 18 supraophthalmic)

MS = 64 wk (infra-ophthalmic infusion) vs 49.5 wk (supra-ophthalmic infusion)

240 mg/m2 BCNU q5–6 wk

Hochberg et al. [60]

IA vs IV ACNU

Prospective, randomized, Phase III

82 (42 IA vs 40 IV)

MS = 59 wk (IA) vs 56 wk (IV); median PFS = 24 wk (IA) vs 45 wk (IV); no significant difference in either outcome

80 mg/m2 ACNU q 6 wk concomitant with RT; IA ACNU was given for 3 doses before given IV

Kochii et al. [20]

CP + ACNU vs Cisplatin + BCNU

Prospective randomized

30 (30 IA vs 30 IV)

MS = 18.3 mo (IA) vs 18.6 mo (IV)

CP 200 mg/m2 and ACNU 100 mg/m2 every 5 wk (IA); BCNU 160 mg/m2 and cisplatin 90 mg/m2 every 5 wk (IV)

Silvani et al. [61]

IA cisplatin + RT

Feasibility study

22 (20 GBM vs 2 AA)

MS = 58 wk (range 14–226); IA cisplatin does not confer survival benefit

60 mg/m2 cisplatin dose  3 doses; most common SE nausea and vomiting with transient neurologic SE

Fountzilas et al. [62]

Grade IV primary GBM studies

Combined grade III and grade IV malignant glioma studies

Carmustine, procarbazine, lomustine, vincristine IA nimustine postop, preRT

West et al. [63]

Retrospective

22

MS = 8 mo (GBM and AA)

150 mg ACNU q 6 wk; systemic SE include asymptomatic thrombocytopenia and leukopenia; ocular toxicities occurred in 3 pts

Vega et al. [71]

Y.R.S. Su et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx

Please cite this article in press as: Su YS et al. Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci (2016), http://dx. doi.org/10.1016/j.jocn.2015.10.019

Table 1 Summary of endovascular therapy for gliomas reported in the literature

Recurrent malignant gliomas

27 (10 GBM vs 17 AA)

65% of AA vs 30% of GBM pts responded to trmt; MS = 21 mo (AA) vs 10 mo (GBM). MS of nonresponders = 9 mo

For inoperable tumors; 100 mg/m2 ACNU q 6 wks  3 doses; 6 pts had acute neurological SE, most common were ophthalmic SE

Chauvenic et al. [64]

IA vs IV HECNU and RT

Phase II

40 (33 GBM vs 6 AA)

MS = >30 mo (AA) vs 10.5 mo (GBM)

Asymptomatic thrombocytopenia and leukopenia; ocular and/or neurologic SE in 20%

Fauchon et al. [65]

IA BCNU w/o RT vs Prior RT + IA BCNU

Phase II

31 (12 with no RT vs 24 with prior RT)

MS = 54 wk (range 21–156 wk) in pts w/o RT vs >54 wk (range 32–261 wk) in pts with prior RT

200 mg/m2 dissolved in ethanol; dose given as short infusions (15–20 minutes) and increased by 50 mg with each succeeding trmt if tolerable; ocular SE occurred in 9 pts

Greenberg et al. [16]

SIACI BCNU

Prospective, nonrandomized

15

MS = 73 wk (range 27–130 wk)

100 mg dose q 6 wk  5 doses; BCNU dissolved in dextrose to reduce CNS toxicity; no leukoencephalopathy reported

Clayman et al. [66]

IA cisplatin and BCNU

Phase II

39 (18 GBM vs 21 AA)

MS = 48 mo (AA) vs 15.5 mo (GBM); 5.6% of pts with >3 vessels supplied had neurologic SE vs 42% of pts had neurologic SE when only 2 vessels supplied

150–200 mg cisplatin and 300 mg BCNU with doses modified by the number of vessels supplied by infused artery

Bobo et al. [67]

IA CP vs IA ACNU

Phase II

42 (20 CP vs 22 ACNU)

Response rate 12.5% (CP) vs 45% (ACNU); MS = 12 mo (ACNU) vs 11.5 mo (CP)

200 mg/m2 ACNU vs 300 mg/m2 CP q 6–12 wk; neurotoxicities occurred more often in pts receiving CP (7/20) than ACNU (3/22)

Fujiwara et al. [68]

SIACI CP infusion

Feasibility study

22 (11 GBM, 11AA)

1 year survival = 5/11 (GBM) vs 6/11 (AA)

Mean CP dose 286 mg/m2; most common SE were seizures with transient neurologic deficits

Qureshi et al. [69]

IA CP vs IA MTX with BBB disruption

Phase II

20 GBM, 54 AA

MS = 13.9 mo (AA) vs 9.1 mo (GBM)

400 mg/m2 IA CP vs 5,000 mg MTX; both groups combined with IV etoposide and IV cyclophosphamide

Fortin et al. [41]

IA cisplatin pre-RT

Phase II

22 (13 GBM vs 9 AA)

33% of AA pts vs 54% of GBM pts responded to trmt; median TTP = 225 d (responders) vs 66 d (nonresponders)

75 mg/m2 dose q 4 wk  4 doses; most common SE = high-frequency hearing loss, 2 pts had post-infusion seizures

Dropcho et al. [70]

SIACI BV (naïve vs prior exposure) with BBB disruption

Phase I

30 (19 naïve vs 11 prior exposure)

MRI showed median reduction in tumor area enhancement of 34.7% (naïve) vs 15.2% (prior exposure) and volume reduction of 46.9% (naïve) vs 8.2% (prior exposure)

No grade III or IV adverse events; no deaths. Neurologic SE = seizures (2) and procedurerelated stroke (1)

Boockvar et al. [19]

IA ACNU at tumor recurrence

Retrospective

18

MS = 6 mo (GBM) and 12 mo (AA)

Pts received prior surgery, RT, +/- chemo

Vega et al. [71]

IA cisplatin

Phase II

35 (20 GBM vs 15 AA)

34% pts responded; MS = 35 wk (responders) vs 27.5 wk (all)

60 mg/sq m dose as continuous dose  dose range 1–7; 63% pts had SE, most common were nephrotoxicity and ototoxicity

Mahaley et al. [72]

IA BV with BBB disruption

Phase I

14 (GBM)

Median PFS = 10 mo MS = 8.8 mo

Pts failed RT and TMZ. Received single dose IA BV (2–15 mg/g) followed by standard IV BV

Burkhardt et al. [3]

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AA = anaplastic astrocytoma, ACNU = 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride, BBB = blood-brain barrier, BCNU = carmustine, btwn = between, BV = bevacizumab, CNS = central nervous system, CP = carboplatin, d = days, GBM = glioblastoma multiforme, HECNU = 1-(2-hydroxyethyl)chloroethylnitrosourea, IA = intra-arterial, IV = intravenous, max = maximum, mo = months, MS = median survival, MTX = methotrexate, PFS = progression free survival, postop = postoperative, pts = patients, RT = radiotherapy, SE = side effect, SIACI = selective intra-arterial cerebral infusions, TMZ = temozolomide, trmt = treatment, TTP = time to tumor progression, vs = versus, wk = weeks, w/o = without, y = years, 5FU = 5-fluorouracil.

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Please cite this article in press as: Su YS et al. Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci (2016), http://dx. doi.org/10.1016/j.jocn.2015.10.019

IA ACNU and RT

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new research and technological innovations may change the therapeutic landscape. 2.1. Embolization and devascularization Preoperative embolization and devascularization of hypervascular brain tumors has exciting clinical potential [9]. Indeed, use of this technique for the operative management of vascular tumors, such as meningiomas, hemangioblastomas, and paragangliomas, has been shown to reduce surgical morbidity with less blood loss, decreased operative time, and increased likelihood of complete resection [10,11]. Fortunately, because most hypervascular tumors are extra-axial and derive their dominant vascular supply from the external carotid system, they can be embolized relatively easily and safely. Unfortunately, because malignant gliomas are intra-axial tumors, they are more challenging to embolize as their feeding vessels are often more distal and narrow, and involve a more tortuous path off the main arteries with angiographic evidence of only a diffuse blush [11]. Furthermore, the available literature of both case reports of embolization and/or clinical studies on the efficacy of embolization in malignant gliomas is sparse and mainly includes cases with demonstrated arteriovenous shunting within the glioma [12,13]. However, technical considerations should include the presence of anastomoses with the vertebral or external carotid arteries, the caliber of tumor vessels, rate of blood flow, and rate of injection to ensure delivery of the embolic agent into the tumor. Multiple agents can be used to devascularize tumors. Though they are not currently used for malignant gliomas, these agents include clots, muscle, silk, Gelfoam (Pfizer, New York, NY, USA), polyvinyl alcohol foam (Ivalon; Fabco, New London, CT, USA), and liquid embolics. Gelfoam, when used as a powder, can enter deep into the pre-capillary or capillary vascular bed of tumors, resulting in extensive tumor necrosis [14]. However, the powder form can also penetrate the pre-capillary supply of cranial nerves, leading to significant deficits. It is particularly important to monitor for external-to-internal carotid anastomoses when planning to embolize with Gelfoam powder. Ivalon is another popular endovascular embolic, due to the ease of suspending the particles into contrast material for injection. One particular advantage of Ivalon is that the particles stop before reaching the capillaries of normal tissue, leading to fewer side effects. Potential complications with endovascular embolization include reflux of the embolic material and the risk of rupture of either a tumor vessel or feeding artery, leading to significant hemorrhage. While microcatheters have reduced the incidence of complications, ischemia can still occur if the embolic agent refluxes and enters the cerebral circulation or travels through an anastomoses to another region of the brain. 2.2. IA drug delivery IA delivery of drugs is not a new concept. In fact, the first study examining its use in patients with head and neck cancers was published in 1950 [15]. However, the early application of IA-infused chemotherapeutic agents through either the carotid or vertebral arteries resulted in significant neurotoxicity, often outweighing treatment benefits [16,17]. As such, IA techniques have only recently resurfaced, with technological advances such as microcatheters. These innovations facilitate targeted intracerebral catheterization and selective intra-arterial cerebral infusions (SIACI). Super-selective intracerebral catheterization has long been used in the treatment of vascular diseases, such as arteriovenous malformations and stenosis, but has only recently been explored for tumor management. Compared to non-selective IA delivery into the carotid or vertebral arteries, SIACI allows for focal delivery of

treatment into tumor-supplying vessels. IA delivery of chemotherapy, especially with the development of microcatheters and SIACI, should expand the repertoire of chemotherapy available to treat malignant gliomas [18,19]. Much of the limited literature on IA-infused chemotherapy for malignant gliomas compares its efficacy to the more standard intravenous (IV) approach, and results thus far have been mixed. A study published in 2000 of IA versus IV chemotherapy for patients newly diagnosed with GBM found a median survival of 59 weeks for IA therapy compared to 56 weeks for IV therapy, a difference that was not significant [20]. Furthermore, a 2006 study compared IA to IV chemotherapy following surgical resection of GBM; the time to progression was found to be 6 months for IA chemotherapy versus 4 months for IV chemotherapy [21]. Most recently, a 2014 review of IA chemotherapy trials for GBM found an overall lower number of adverse events in IA chemotherapy versus IV therapy even though both median progression free survival and overall survival remained higher with IV therapy [22]. These published studies are difficult to interpret because they each utilize their own treatment protocols, use a variety of different chemotherapeutic agents in varying combinations, and examine disparate populations. However, one can reasonably argue that IA chemotherapy is at clinical equipoise with IV chemotherapy. More research into optimizing dosing levels and infusion techniques may lead to the focal, effective therapy that IA drug delivery has always promised. Looking ahead, there is great potential in combining the principles of IA drug delivery with the latest insights on the molecular basis of malignant gliomas. Indeed, studies on the molecular pathways of malignant gliomas have revealed that tumors such as GBM are highly heterogeneous in terms of their genetic makeup, thus making their response to a single agent inadequate and dictating the necessity for multimodal therapy. Understanding the unique molecular pathogenesis of these tumors is fundamental to developing therapies that are more effective. For instance, it is known that the epidermal growth factor receptor (EGFR) is overexpressed and amplified in nearly half of all GBM [23,24]. Subsequent studies on the small molecules gefitinib and erlotinib have found them to inhibit the activation of EGFR, leading to antiproliferative and antiinvasive results [25,26]. Another agent, cetuximab, is a monoclonal antibody that blocks the activation of EGFR and has also been shown to decrease growth of GBM tumor cells [27]. Unfortunately, all three EGFR-targeting agents have thus far shown limited clinical benefits in human trials [28–32]. Perhaps exploring the use of these and other molecular targeting agents with IA delivery may produce previously unseen results, particularly as much of the limited success of early studies may be due to inadequate dosing and poor delivery of the agent. Another novel therapeutic strategy where IA infusion may stand to contribute is oncolytic virotherapy. This is a technique based on the delivery of mesenchymal stem cells infected with the adenovirus ICOVIR-5, which targets tumor stroma through signaling with mesenchymal stem cells and then selectively replicates in glioma cells [33]. Although only a few experimental case reports currently exist on oncolytic virotherapy, most work has been done using IV delivery or stereotactic intraparenchymal delivery, which has been restricted by limited diffusion of the viruses to the entirety of the tumor. IA infusion may increase the number of mesenchymal stem cells delivered to the tumor. Furthermore, IA delivery would avoid vascular complications, including hemorrhage or edema, that may secondary to stereotactic injection. 2.3. BBB disruption The BBB is part of the brain capillary layer that is composed of tight junctions, efflux pumps, and astrocyte podocytes, and it

Please cite this article in press as: Su YS et al. Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci (2016), http://dx. doi.org/10.1016/j.jocn.2015.10.019

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restricts passage of ionized molecules with molecular weights greater than about 180 Da [34]. It is commonly thought that the BBB impedes delivery of many chemotherapeutic agents, which generally range from 200–1,200 Da [35]. Because of the restrictions associated with the BBB, it has been proposed that combining IA delivery with BBB disruption would allow for greater delivery of the desired agent to malignant gliomas. Indeed, IA chemotherapy combined with osmotic disruption or bradykinin administration are two examples of such an approach. Osmotic disruption of the BBB was first reported in 1972 [36]. This strategy involves infusion of a hypertonic solution (for example, mannitol) into the cerebral arteries; the newly formed osmotic gradient forces water out of endothelial cells, causing them to shrink while simultaneously increasing permeability of the BBB. This weakening of the BBB has been shown to increase the levels of successfully infused chemotherapy by up to 90-fold [37]. However, there exists some concern about this therapeutic approach, and it mainly centers on whether the hyperosmotic infusion will significantly disrupt areas of the BBB where normal brain tissue resides, thus resulting in unintended neurotoxicity [38–40]. While this concern is valid and warrants careful monitoring, human studies have shown osmotic disruption of the BBB to be therapeutically beneficial. Indeed, a 2005 study of patients with malignant gliomas found that pretreating with mannitol prior to IA carboplatin delivery significantly increased median survival to 154 weeks compared with a median survival of 90 weeks with IA carboplatin alone [41]. More recently, a 2012 study used IA bevacizumab after mannitol infusion in patients with recurrent GBM failing standard treatment with radiation and temozolomide; the result was an encouraging median progression free survival of 10 months [3]. Similarly designed studies of other types of brain tumors have also yielded beneficial results, including one study of patients with central nervous system lymphoma showing improved average survival from 17.8 months to 44.5 months [42]. With less success than osmotic disruption, naturally occurring bradykinin and synthetic analogs have also been explored as BBB disrupters to use in conjunction with IA chemotherapy. Bradykinin analogs, which mimic endogenous vasoactive peptides, came under investigation when it was observed that they cause capillaries in tumor tissue to increase their permeability compared to vessels in normal brain tissue [43,44]. An interest then formed in administering bradykinin to improve chemotherapy uptake into tumors [45]. Early encouragement came when a 1996 study examining the use of lobradimil, a synthetic bradykinin, in conjunction with IA delivery of carboplatin, increased the delivery of the chemotherapeutic agent two-fold [46]. However, the scant literature that exists indicates that, although it is clinically safe to administer bradykinin in combination with IA chemotherapy for malignant gliomas, tumor response outcomes are variable or uncertain [47]. Pairing this strategy with traditional IV chemotherapy for treating pediatric brain tumors was also unsuccessful in improving outcomes [48]. Perhaps the BBB response to bradykinin analogs may be too non-specific and, therefore, may not be therapeutically meaningful until tumor-specific delivery can be improved. In the future, IA drug delivery may be paired with one of a number of emerging and promising techniques designed to overcome the BBB. At varying stages of feasibility, these techniques include MRI-guided focused ultrasound (FUS), viral-mediated circumvention, liposomal delivery, carrier molecules, convection-enhanced drug delivery (CEDD), or P-glycoprotein targeting and modulation [49]. Of these techniques, only CEDD and P-glycoprotein targeting have undergone clinical trials at the time of writing. It is also noteworthy that FUS has successfully transported a number of chemotherapeutic agents across the BBB [50–52]. Additionally, a 2014 study found that FUS could augment the uptake of nanopar-

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ticles coated with anti-epidermal growth factor into glioma cells [53]. While covering these advanced techniques to overcome the BBB is beyond the scope of this review, it is important to recognize that as new clinical studies and technologies are considered, IA drug delivery specifically, and endovascular principles more broadly, should not be ruled out as a means to increase efficacy. 3. Discussion The potential benefits of endovascular delivery to treat gliomas are plentiful, including targeted delivery of anti-neoplastic agents, a voidance of systemic toxicity, and capacity for multiple treatments with a relatively low degree of associated morbidity. Nevertheless, concerns and challenges surrounding endovascular therapy for malignant gliomas persist. First and foremost, the safety of IA delivery requires further evaluation. While current data exist for the safety of several chemotherapeutic agents, it is difficult to translate these data into trials that will give promising efficacy, given that standardization of agent dosages remains to be seen, in addition to establishment of standard methods of the catheterization technique. As with all modalities, employment of an endovascular technique in the intracerebral setting does not come without risks. Complications such as vessel rupture or cerebrovascular accident, albeit rare, are to be acknowledged. Such complications may restrict the choice of vessel used. In particular, side branches of distal arteries, rather than main branches, generally feed malignant gliomas, and as such, superselective embolization and chemotherapy may not be technically feasible without an unacceptable degree of risk to the patient. Similarly, access to centers offering such techniques is currently less prevalent than for traditional modes of glioma therapy, such as radiation and chemotherapy. Endovascular techniques also pose an intraoperative risk, including rupture of distal vessels with the balloon catheter during placement. Refinement and optimization of the technical nuances involved in endovascular drug administration will occur as further experience is gained and more robust studies are published. Lastly, while not included in any of the above categories for endovascular therapy, the considerable interest in coupling endovascular techniques with brain mapping technologies to aid in more aggressive tumor resections is notable. Preoperative endovascular brain mapping with a superselective Wada test was first reported in 2006 [54]. Using this approach, when the targeted brain region is determined to have no functional activity, a second mapping agent is injected into the same microcatheter to stain the corresponding brain. This stain can be utilized in tumor resections to ensure total resection and avoidance of neurologic deficits. An advantage of endovascular brain mapping techniques over stereotactic-guided mapping includes improved information about spatial resolution and functionality that is not currently provided with stereotactic mapping. Furthermore, especially when coupled to craniotomy resections, stereotactic-guided imaging can deviate from real-time dissection, as the brain will shift with resection, cerebrospinal fluid drainage, and opening of the cranial cavity. In contrast, endovascular brain mapping does not alter throughout the resection. 4. Conclusion Effective therapies against malignant gliomas remain elusive, as these tumors progress rapidly and virtually always recur. While new therapies targeting the underlying mechanisms of tumorigenesis are actively sought, endovascular treatment provides a relatively novel approach. Endovascular therapy harnesses the efficacy of previously employed agents and techniques in a repur-

Please cite this article in press as: Su YS et al. Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci (2016), http://dx. doi.org/10.1016/j.jocn.2015.10.019

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posed manner, and does so while circumventing previously common limitations, such as systemic toxicity and the inability to traverse the BBB, in a fashion compatible with a multimodal treatment strategy. Challenges certainly exist with endovascular therapy for malignant glioma, as common endovascular approaches, such as embolization and IA drug delivery, have yet to deliver effective results. However, the confluence of refinements in the endovascular technique – particularly when paired with BBB disruption – along with advancing molecular information about the malignant gliomagenesis, helps poise endovascular neurosurgery as a leading modality in the 21st century care of malignant gliomas.

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Please cite this article in press as: Su YS et al. Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci (2016), http://dx. doi.org/10.1016/j.jocn.2015.10.019