clinical trials in brain

8/4/2019 Clinical Trials in Brain

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Cl i ni c a l T ri a l s i n Bra i nTumor Surgery

Jason M. Hoover, MDa, Susan M. Chang, MDb,Ian F. Parney, MD, PhDa,*

Central nervous system tumors represent

a continued medical and surgical challenge.

Primary intra-axial brain tumors, more specifically

gliomas, have an annual incidence of approxi-mately 14 per 100,000.1,2 Glioblastoma is the

most frequent and malignant histologic subtype

(World Health Organization [WHO] grade IV).

Surgery has an established role in the diagnosis

and treatment of brain tumors and forms a key

part of standard therapy along with radiation and

chemotherapy. Outcomes for most brain tumor

patients, however, remain humbling and continued

efforts to improve and refine brain tumor treatment

(including surgery) are needed. This article focuses

on clinical trials in primary intra-axial brain tumorsurgery, including a review of outcome data with

standard surgical maneuvers, techniques to maxi-

mize safe surgical resection, and trials of surgically

delivered therapeutics.

STANDARD NEUROSURGICAL TECHNIQUES

Standard neurosurgical techniques in brain tumor

management can be divided into those primarily

directed at diagnosis (ie, techniques for biopsy)

and those directed at tumor debulking (ie, tech-

niques for craniotomy and resection). This sectionreviews clinical trials of these standard tech-

niques, including outcome studies.

Frame-Based Stereotactic Biopsy

Stereotactic biopsy can be defined as biopsy of

intracranial lesions through a burr hole using

stereotactic target coordinates determined on

prebiopsy imaging. Stereotactic biopsy tech-

niques were first developed using rigid frames

attached to a patients skull.3 A rigid fiducial

marker box is attached to the frame base beforeimaging (CT or MR imaging), thus defining the

stereotactic space to determine the target, entry

point, depth, and trajectory based on X, Y, and

Z coordinates and a Cartesian system. The fidu-

cial marker box is replaced by a stereotactic

guide system attached to the frame that directs

a biopsy needle from the entry point to the

target along the selected trajectory to the depth

calculated by the system (Fig. 1 ). Frame-based

stereotactic needle biopsy can be performed

with local or general anesthetic. The techniqueis generally safe and has a high chance of

obtaining diagnostic material. Diagnostic yields

are 91% to 98.4% with transient morbidity of

2.9% to 9%, permanent morbidity of 1.5% to

5%, and mortality of approximately 1% in

modern series.46 Small, deep lesions in

eloquent brain are associated with higher rates

of morbidity and nondiagnosis. In addition, the

number of separate trajectories needed to

obtain diagnostic material has been associated

with increased morbidity.5 Finally, there remains

the potential for sampling error with stereotacticbiopsy. In a series of patients at the MD Ander-

son Cancer Center who underwent craniotomy

and tumor resection after previously undergoing

stereotactic biopsy for glioma, the final patho-

logic diagnosis changed in 38% once further

tissue was available.7 This was largely ac-

counted for by differences in tumor grade.

a Department of Neurologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAb

Department of Neurologic Surgery, University of California, 505 Parnassus Avenue, San Francisco, CA 94143,USA* Corresponding author.E-mail address: [email protected]

KEYWORDS

Brain tumor Gliomas Central nervous system Cytoreductive surgery

Neuroimag Clin N Am 20 (2010) 409424doi:10.1016/j.nic.2010.04.0061052-5149/10/$ see front matter 2010 Elsevier Inc. All rights reserved. n

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Frameless Stereotactic Needle Biopsy

Frameless stereotactic biopsy performed using an

intraoperative neuronavigation system, such as

Stealth, BrainLab, or ISG Wand, is increasingly

common.8 Preoperative imaging (MR imaging or

CT) is obtained after placing multiple adhesive

fiducial markers on the patients scalp. This infor-

mation is transferred to an intraoperative

computer connected to a binocular sensing device

(eg, infrared camera) that can register the preoper-

ative imaging in stereotactic space using the fidu-

cial markers (Fig. 2 ). Alternatively, some systems

register preoperative imaging using bony land-

marks. Once the imaging and patient are regis-tered, a viewing wand or other tool can be used

to demonstrate the underlying anatomy in 3-D.

An entry point, trajectory, depth, and target can

then be determined for the biopsy. A guide system

attached to the skull or head holder keeps the

biopsy instrument steady, allowing careful depth

measurement and strict adherence to theproposed trajectory. Frameless stereotactic nee-

dle biopsy is often performed under general

anesthetic.

Frameless stereotactic biopsy has been exten-

sively reported in recent years, with diagnostic

yields of 85% to 91% and permanent morbidity

rates of 3% to 6%.810 Studies with imaging

phantoms have suggested that frameless and

frame-based stereotactic biopsy accuracy are

comparable.11 Fiducial markers or surface land-

marks used to register images for frameless

systems may shift, however, during positioning

for surgery. This is not an issue for rigid frame-

based systems. Thus, some investigators advo-

cate continued reliance on frame-based biopsy

Fig. 1. Postcontrast T1-weighted MR imaging and reconstructions of a 73-year-old right-handed man who pre-sented with a right hemiparesis secondary to an enhancing mass in his left insular cortex and basal ganglia.The hyperintense fiducial markers from the Compass stereotactic frame can be seen surrounding his head. Theentry point, trajectory, and target are shown in the upper and lower right images. The final pathology was GBM.

Hoover et al410


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for small or deep lesions. Furthermore, there are

potential advantages to frame-based biopsies in

terms of reduced use of anesthesia, operating

room, and hospital resources,10 although this

may vary with individual practice patterns. Incontrast, some investigators have concluded that

frameless stereotactic biopsy is comparable with

frame bases with regard to diagnostic yield and

complications but has distinct advantages.

Although a recent series from the Johns Hopkins

Hospital found no significant differences in diag-

nostic yield or complications, more than one nee-

dle trajectory was required more frequently to

obtain diagnostic tissue from cortical lesions withframe-based compared with frameless stereo-

taxy.8 In other studies, increased number of nee-

dle trajectories has been strongly associated with

increased morbidity.5 The Johns Hopkins

Fig. 2. (A) Axial T1-weighted and T2-weighted postcontrast images and (B) frameless stereotaxic biopsy plan(using the Stealth system) for an 18-year-old right-handed woman presenting with diplopia secondary toa partially enhancing mass in the left medial thalamus and midbrain tectum. The final pathology was primitiveneuroectodermal tumor.

Clinical Trials in Brain Tumor Surgery 411


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response to adjuvant therapy with more extensive

resection. The definition of maximal safe resection,

however, differs widely among neurosurgeons.

The authors reviewed the literature from the past

20 years using a similar strategy to that described

previously for malignant gliomas. A PubMed

search was performed using combinations of thekey words, low-grade, grade I, diffuse,

glioma, astrocytoma, oligodendroglioma,

oligoastrocytoma, surgery, and outcome. In

addition, further key publications were identified

by cross-references in the resulting articles.

Studies without information on outcome with

varying degrees of resection, where extent of

resection was not determined on the basis of post-

operative imaging or where formal statistical eval-

uation was lacking, were excluded. Similarly,

studies including children or patients with grade

I, III, or IV tumors were excluded unless these pop-

ulations were analyzed separately. In addition,

studies with short median follow-up (


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(magnetic resonance spectroscopy [MRS], cere-

bral perfusion, and positron emission tomography

[PET]), which can be used to provide information

about the nature and extent of the tumor itself;

and (2) functional imaging (functional MR imaging,

diffusion tensor imaging, PET, and magnetoence-

phalography), which can provide informationabout adjacent eloquent brain. This section

reviews recent clinical studies about physiologic

and functional imaging in brain tumor surgery.

Physiologic imagingSeveral imaging modalities have been used to

elucidate information about tumor physiology

that can be beneficial in surgical planning by high-

lighting more aggressive areas or further delin-

eating the extent of tumor beyond enhancing

margins.57 For example, proton-based MRS can

distinguish tumor (increased choline to N-acety-

laspartate [NAA] ratio) from normal tissue (choline:

NAA ratio


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imaging scanners. Furthermore, they can be used

to reregister image-guidance systems. A recent

study from the University of California in Los An-

geles reported a series documenting extent of

resection with varying image guidance and intrao-

perative MR imaging systems.80 As expected,

extent of resection was generally larger with image

guidance than without. Low-field intraoperative or

high-field intraoperative MR imaging alone did not

improve on this but high-field intraoperative MR

imaging with reregistration of a neuronavigation

system resulted in the highest degree of resection

of any combination of image guidance and intrao-

perative imaging systems. (See Fig. 5 for an

example of imaging obtained with high-field intra-

operative MR imaging.)

Electrophysiologic Mapping

Although preoperative functional imaging can be

incorporated into many neuronavigation systems,

intraoperative electrophysiologic mapping remains

the gold standard for identifying functional cortex

and subcortical fiber tracts. This is not a new tech-

nique, having been originally developed by Pen-

field and Boldrey in the 1930s to facilitate

epilepsy surgery.81 It has since been adapted to

a variety of neurosurgical indications, including

intra-axial tumor resection.82,83 It has been sug-

gested that, as long as the resection remains

exclusively within the tumor itself, the risk of

neurologic injury is low. This is not always

possible, however, and data from large prospec-

tive series suggest that functional neurons occur

within tumors adjacent to functional cortex in up

to 8% of cases.84 Mapping motor cortex and

subcortical fibers can be done while patients are

awake or asleep (with appropriate anesthetic

management)85 but speech mapping requires

awake craniotomy and patient cooperation. As

experience has grown with speech mapping in

tumor surgery, it has become evident that thiscan allow aggressive tumor resection in brain

areas traditionally felt to be inoperable due to their

proximity to critical areas for speech. In a recent

prospective series of 250 patients with gliomas,

Fig. 3. (A) Standard axial T1-weighted postcontrast MR imaging of the head demonstrating a right frontal glio-blastoma. (B) Cerebral blood volume/perfusion MR imaging demonstrating increased blood flow (red) inenhancing areas of same glioblastoma. (C) Multivoxel 3-D MRS of the same patient demonstrating increased chol-ine:NAA ratio in tumor and surrounding T2 hyperintensity.



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Berger and colleagues86 reported that critical

speech areas were identified in 58%. One weekafter surgery, speech function was worsened in

22%; it resolved in most patients, however, and

only 1.6% of surviving patients at 6 months

continued to have increased speech deficits.86

Surface cortical electrophysiologic mapping is

useful for identifying appropriate safe entry pointsfor surgical resection. It does not identify subcor-

tical fibers, however, that may deviate from their

surface origin as they pass. For this, subcortical

electrophysiologic mapping is critical, particularly

Fig. 4. (A) Standard axial T1-weighted postcontrast MR imaging of the head demonstrating a left parietal glio-blastoma. (B) Functional MR imaging demonstrating areas of activation (red and yellow) with right ankle andhand motor tasks anterior and superior to the tumor. (C) DTI demonstrating displacement of white matter tractsby the tumor. (D) Frameless stereotactic images of the same patient with motor areas for right hand (green) andankle (pink) superimposed. The viewing wand (blue) has been placed at a critical motor area for right hand func-tion identified by intraoperative electrical stimulation mapping with a bipolar electrode. Note that this corre-sponds to only a portion of the larger area identified by functional MR imaging, suggesting that functionalMR imaging was sensitive but not specific for motor function in this case.

Hoover et al416


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for motor mapping,85 and uses techniques similar

to surface mapping and can be used intermittently

as resection proceeds.

Fluorescence-Guided Resection

Fluorescence-guided resection relies on adminis-

tration of a pharmacologic agent that localizes totumor but not surrounding brain and fluoresces

when exposed to light of the appropriate wave-

length. Tumor resection can be guided by the

fluorescence seen at surgery, potentially allowing

a surgeon to identify tumor tissue that otherwise

might not be obvious at craniotomy. Fluores-

cence-guided surgery for brain tumors has been

used most commonly with 5-ALA. 5-ALA is orally

available and accumulates in glioma tissue where

it is metabolized to protoporphyrin IX and fluo-

resces pink when exposed to light at 375 to

440 nm.87 Stummer and colleagues22 have pub-lished results of a multicenter randomized

controlled trial comparing 5-ALA fluorescence-

guided resection with standard white light resec-

tion in 322 newly diagnosed GBM patients.

Patients undergoing fluorescence-guided

resection were more likely to have a gross total

resection (65% vs 36%, P


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Brachytherapy

Brachytherapy can be defined as implanting inter-

stitial radioactive sources directly into the tumor at

surgery to allow delivery of local high-dose irradia-

tion while leaving surrounding tissues relatively

spared. Iodine 125 and iridium 132 are commonlyused sources. At least two forms have been investi-

gated in malignant glioma treatment: temporary/

high-dose brachytherapy and permanent/low-

dose brachytherapy.89,90 Although initial studies

with high-dose temporary brachytherapy were

promising, they failed to show benefit in a random-

ized controlled trial.88 Single-arm studies of radical

resection of recurrent malignant gliomas followed

by permanent low-dose brachytherapy have shown

modest efficacy.91,92 GliaSite, another method for

delivering temporary brachytherapy, has also

been investigated. In this method, an inflatableballoon catheter is placed in the resection cavity

at craniotomy for a recurrent malignant glioma.93

An aqueous solution of organically bound 125I is

delivered to the balloon via a subcutaneous port 1

to 2 weeks after craniotomy and removed after

3 to 6 days. Gliasite has been safe and rela-

tively promising in single-arm studies.9395

These results remain to be evaluated, however, in

randomized studies.

Chemotherapy with Biodegradable Wafers

Several strategies have been used to deliver

chemotherapeutic agents surgically to patients

with malignant gliomas. Initial efforts focused on

direct injection into tumor or surrounding paren-

chyma had limited efficacy but relatively high

toxicity.96 As an alternative to bolus injection,

Brem and colleagues97 developed methods to

line malignant glioma resection cavities with

biodegradable wafers impregnated with chemo-

therapeutic agents. In randomized controlled

trials, recurrent malignant glioma patientsreceiving carmustine (BCNU)-impregnated poly-

mer wafers had modest but significantly prolonged

median survival compared with patients who

underwent simple resection (31 weeks vs 23

weeks).9698 In the largest study, a statistical

survival benefit persisted for up to 3 years.99 In

a recent institutional review, 1013 patients under-

going craniotomy for malignant astrocytomas

over a 10-year period at Johns Hopkins Hospital

were reviewed. Perioperative morbidity (within 3

months) and overall survival were assessed. Of

1013 patients who had craniotomies for malignantastrocytoma, 288 (28%) received Gliadel wafers

(250 patients had GBM and 38 patients had AA/

anaplastic oligodendroglioma [AA/AO]). Patients

receiving Gliadel were older and more frequently

underwent gross total resection (75% vs 36%).

The patients in Gliadel versus non-Gliadel cohorts

had similar perioperative morbidity. For patients

receiving Gliadel for GBM, median survival was

13.5 months after primary resection (20% alive at

2 years) and 11.3 months after revision resection

(13% alive at 2 years). For patients receiving Glia-del for AA/AO, median survival was 57 months

after primary resection (66% alive at 2 years) and

23.6 months after revision resection (47% alive at

2 years).100

Convection-Enhanced Delivery

There remains concern as to whether or not

chemotherapy-impregnated wafers are the most

effective way to deliver therapeutic agents locally

to patients with malignant gliomas at surgery.

Just like bolus injection, chemotherapy wafers

rely on diffusion to carry their agents into the

surrounding brain parenchyma. Concerns have

been raised that delivery via chemotherapy wafers

may be too limited. As an alternative, Oldfield and

colleagues101,102 at the National Institutes of

Health pioneered an approach, termed, convec-

tion-enhanced delivery (CED). Between 1 and 3

small-diameter sialastic tubes are placed stereo-

tactically in the tumor itself or in brain parenchyma

surrounding a resection cavity and tunneled

subcutaneously through the scalp. Therapeuticagents are then delivered via slow constant infu-

sion (eg, 0.2 mL/h) through these catheters over

3 to 5 days postoperatively. The pressure from

the slow infusion sets up a local convection current

within the brain from the catheter tip (convection-

enhanced) that results in a large volume of

distribution for the agent in question. In ideal

circumstances, an entire lobe can be perfused

from a single catheter.

Most CED clinical trials to date have focused on

small fusion proteins that have linked an intracel-lular toxin (eg, pseudomonas exotoxin or diph-

theria toxin) to a ligand for surface receptors that

are overexpressed on malignant glioma cells (eg,

interleukin-13 or transferrin). Promising results

from several phase I and II studies have been re-

ported in newly diagnosed and recurrent malig-

nant gliomas.103,104 These therapies have

potential for local inflammatory reactions that can

be followed on post-treatment MR imaging scans

and occasionally require treatment.105 Two large

multicenter randomized controlled trials have

been completed in patients with recurrent glio-blastomas (PRECISE and TransMID). These trials

demonstrated that CED of these agents was safe

and well tolerated. Unfortunately, they did not

show any survival benefit. To date, these results

Hoover et al418


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have only been reported as press releases. Exper-

imental efforts are ongoing to track and improve

delivery by CED106 and to expand the types of

agents that can be delivered using this

approach.107

Oncolytic Viral Vectors and SuicideGene Therapy

Oncolytic virus therapy is a novel treatment option

for GBM patients. These viruses are naturally

occurring or genetically engineered viruses with

a predilection to infect and kill tumor cells while

leaving normal cells unharmed. They are derived

from a variety of viruses, including herpes simplex

virus (HSV-1), adenovirus, reovirus, measles, and

Newcastle disease virus. The mechanisms under-

lying their relative tumor specificity are not always

clear. Although work is ongoing to develop onco-

lytic viruses that can be systemically delivered,

clinical trials so far in malignant gliomas have

been limited to viruses that are delivered locally

at surgery.108110 Oncolytic measles virus strains

derived from the Edmonston vaccine lineage serve

as a good example of the types viruses used in

this manner. They have been effective in preclin-

ical studies when delivered to intracranial

tumors.111,112 This strain was engineered to

express the marker peptide measles viruscarci-

noembryonic antigen (MV-CEA) and MV-CEAlevels can serve as a correlate of viral gene expres-

sion. In support of a phase I clinical trial of intratu-

moral and resection cavity administration of

MV-CEA to patients with recurrent gliomas, safety

was demonstrated in rhesus macaques. The

investigators found that more than 36 months

from study initiation there had been no clinical or

biochemical evidence of toxicity, including lack

of neurologic symptoms, fever, or other systemic

symptoms and lack of immunosuppression.113

This approach is currently in phase I clinical trials.Finally, Ram and colleagues114 have evaluated

the use of sitimagene ceradenovec (Cerepro) and

ganciclovir gene therapy in the treatment of

primary high-grade gliomas. This differs from

a true oncolytic virus approach in that the virus

has no inherent anticancer properties. Instead,

a genetically engineered adenovirus delivers

a suicide gene (HSV thymidine kinase) that kills

tumor cells only when they are exposed to ganci-

clovir. The primary outcome measures for this

randomized controlled trial are time from surgery

to reintervention or death. Although data analysesare not complete, preliminary results suggest that

patients in the Cerepro arm have a statistically

significant improvement in outcome. Further data

will be reported as they become available.114

SUMMARY

Brain tumor surgery, specifically glioma surgery,

spans a broad range of pathologies and tech-

niques. There is a continued need to improve the

therapies available for treating these devastating

tumors. As reviewed in this article, many clinicalstudies have examined new surgical techniques

to perform and guide brain tumor biopsy and

resection, the value of cytoreductive surgery, and

the potential to introduce novel therapeutic agents

locally at surgery. These studies have expanded

the breadth of knowledge regarding optimal

surgical approaches and have opened the door

to new technologies that will hopefully have an

impact on survival for patients with gliomas in the

future.

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