VOLUME 34 • NUMBER 9

May 15, 2012

A BIWEEKLY PUBLICATION FOR CLINICAL NEUROSURGICAL

CONTINUING MEDICAL EDUCATION

Malignant Gliomas
Part II: Gliomagenesis and Glioblastoma Therapy
Nicholas A. Butowski, MD, and Mitchel Berger, MD
Learning Objectives: After participating in this CME activity, the neurosurgeon should be better able to:
1. Categorize the standard of care for newly diagnosed and recurrent glioblastoma.
2. Evaluate the challenges and advances in molecular biology of high-grade glioma.
3. Assess the challenges and advances in the care of patients with high-grade glioma, particularly as they pertain to surgical resection,
radiotherapy, and chemotherapy.

This article is the second of 3 parts.
This article is the second part of three detailing the state-
of-the art treatment for patients with high-grade glioma. This
installation reviews theories of gliomagenesis, standard treat-
ment for patients with high-grade glioma, and strategies at
tumor recurrence including novel therapies.
Gliomagenesis
High-grade glial tumors originate from glia, Greek for
“glue,” brain tissue originally viewed as providing subsidiary
functions to neural cells such mechanical support, maturation
guidance, immune functions, and waste disposal. Now it is
thought that glial cells function analogous to equal partners
to neurons and are intricately involved in complex processes
like neurotransmission. Brain tumors occur as the result of
mutations in genes that control normal biologic processes.
Dr. Butowski is Associate Professor, Department of Neurological
Surgery, Division of Neuro-Oncology, and Neuro-Oncologist, Brain
Tumor Research Center; and Dr. Berger is Kathleen M. Plant Dis-
tinguished Professor and Chairman, Department of Neurological
Surgery, and Director, Brain Tumor Research Center, University of
California, San Francisco, 400 Parnassus Ave, #0372, San Francisco,
CA 94143; E-mail: butowski@neurosurg.ucsf.edu.
All faculty and staff in a position to control the content of this CME
activity and their spouses/life partners, if any, have disclosed that
they have no financial relationships with, or financial interests in, any
commercial organizations pertaining to this educational activity.
These mutations trigger the activation of oncogenes or the
silencing of tumor-suppressor genes.
Understanding the genetic and epigenetic alterations in high-
grade gliomas may lead to better understanding of gliomagenesis,
tumor behavior, and provide therapeutic targets. For instance,
overexpression of growth factors like epidermal growth factor
receptor (EGFR) and platelet-derived growth factor receptor
(PDGFR) activates the phosphatidylinositol 3-kinase (PI3K)/mam-
malian target of rapamycin (mTOR) pathways, leading to sup-
pression of apoptosis and increased cellular proliferation. Further
dysregulation results in upregulation of vascular endothelial
growth factor (VEGF) and resulting angiogenesis. Glioma invasion
is promoted through hepatocyte growth factor to the c-MET
receptor. The redundant nature of all of these signaling pathways
remains an area of active research particularly those pathways
that promote motility, thereby allowing glioma cells to invade
deep into brain tissue. This redundancy is chief among the reasons
why tumors recur despite surgery, radiation, and chemotherapy.
Specific molecular targets exploiting cell surface receptors and
signaling molecules activated in growing and migrating cells are
being investigated; however, the high level of redundancy of cell
signaling, the unknown influence of the microenvironment, and
the lack of modeling systems that exhaustively reflect the unique
nature of glioma in the brain suggest that this area will remain
under investigation for some time to come.
Category: Tumor
Key Words: Glioblastoma, Glioma, Brain tumor

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 Recent evidence suggests that cells, at times called cancer-
propagating cells or cancer stem cells, promote or produce high-
grade gliomas. These cells are believed to constitute only a minor
part of the total cell population within brain tumors but may
assist in tumor differentiation, proliferation, and angiogenesis.
These cells give the tumor its ability to evade therapy because
in comparison with the bulk of more differentiated tumor cells,
they are more efficient at repair of damaged DNA in response
to radiation. Stem cells also possess increased expression of
transporters that pump out chemotherapeutic agents for
chemoresistance. Signaling pathways involved in neuronal
and glial differentiation, like Notch and Sonic hedgehog have
also been implicated in gliomagenesis. However, the “cell of
origin” for the formation of gliomas remains unknown. As
described, one line of thought hypothesizes that neural stem
cells or neural progenitors undergo transformation for unknown
reasons and give rise to tumors. Other evidence coincides with
the mutation-induced dedifferentiation of mature brain cells.
Perhaps both or either are true depending on the patient? A
more recent theory supports that the extensive heterogeneity
at the cellular and molecular levels may arise from various cell
populations that establish a complex “cancer network” of inter-
actions among each other and with the tumor microenviron-
ment, which eventually strengthens tumor growth and increases
opportunities to escape therapy.
Glioblastomas (GBs) are subdivided into primary and sec-
ondary types based on their molecular profile. Primary GBs typ-
ically occur in patients older than of 50 years and are characterized
by overexpression or mutation of the EGFR, loss of heterozygosity
on chromosome 10q, and PTEN mutation. Secondary GBs gen-
erate from lower grade gliomas and typically occur in younger
patients being characterized by p53 mutations and overexpression
of PDGFR. Mutations in human cytosolic nicotinamide adenine
dinucleotide phosphate (NADPH)–dependent isocitrate dehy-
drogenase-1 and -2 (IDH1 and IDH2) may be an early event
in glioma formation, and are observed in patients with anaplastic
astrocytoma, anaplastic oligodendroglioma, and secondary
GB. It is thought that IDH mutations have an indirect oncogenic
effect through the activation of the hypoxia-inducible factor
(HIF) pathway, a significant step in the metabolic adaptation
of tumors to anaerobic growth and the formation of new blood
vessels. Alternatively, IDH mutations may lead to the ability to
catalyze the NADPH-dependent reduction of ␣-ketoglutarate
to R(-)-2-hydroxyglutarate. Altogether, these findings enable
the stratification of patients on the basis of their molecular
classification as a complement to traditional descriptive-based
categorization.
Such complementary reasoning has been nurtured by The
Cancer Genome Atlas project sponsored by the National Insti-
tutes of Health. This project is integrating expression profile
data and genetic data in an effort to provide better understand-
ing of the genesis of brain tumors. With this aim in mind, pri-
mary GBs from brain tumor centers across the country were
analyzed at the DNA (gene copy number, gene sequencing,
and epigenetic methylation), messenger ribonucleic acid (RNA,
gene expression profile), and micro-RNA (small RNAs that can
regulate expression) levels. Analyses continue, yet initial findings
demonstrate that GBs can be subdivided into 4 subtypes. Com-
parison of the gene-expression patterns from the 4 GB subtypes
with those from cultures of primary murine astrocytes, oligo-
dendrocytes, neurons, and microglia suggest that subtypes
may originate from various cells. With further study, this clas-
sification may pinpoint the best molecular targets within each
subtype, although there seems to be some measure of overlap.
The first subtype, called classical, has a profile of highly pro-
liferative cells. These tumors demonstrate gains on chromosome
7, accompanied by losses on chromosome 10 and frequent focal
losses on chromosome 9, which lead to amplification of EGFR
and loss of PTEN and CDKN2A. Mutations in TP53, neurofibro-
matosis type 1 (NF1), PDGFR, and IDH1 genes are usually lacking.
As a consequence, classical GB may respond to radiation and
chemotherapy because the p53 DNA damage reaction is intact.
At the gene expression level, the classical subtype demonstrates
elevated expression of nestin (NES), a neural precursor and stem
cell marker, and Notch and Sonic hedgehog signaling pathways.
The second subtype, mesenchymal, has an expression profile
associated with mesenchyme and angiogenesis. It overexpresses
CHI3L1/YKL40 and MET genes, astrocytic markers CD44 and

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2
MERTK, and genes in the NF␬B pathway. These tumors also
have inactive NF1, TP53, and PTEN genes. These tumors also
respond to chemoradiation strategies but also may respond to
Ras, PI3K, and angiogenesis inhibitors.
A third subtype, proneural, has an expression profile similar
to that seen with gene activation in neuronal development. This
includes a high level of expression of oligodendrocytic (PDGFRA,
OLIG2, TCF3, and NKX2-2) and proneural (SOX, DCX, DLL3,
ASCL1, and TCF4) development genes. These patients tend to
be younger and overexpression or amplification/mutation of
the gene encoding PDGFR and mutations in the IDH1 gene are
common genetic alterations. The presence of IDH1/2 gene muta-
tions in lower grade gliomas suggests that secondary GB may
belong to this subtype. It is thought that this group may respond
to inhibitors of the HIF, PI3K, and PDGFRA pathways and less
so to radiation or common therapeutic strategies. This fact is
ironic, as survival in the proneural subtype seems slightly better
than in the other 3 tumor subtypes.
The fourth subtype, neural, is not as well-defined, but it has
gene expression signatures similar to those observed in normal
brain tissue, with activation of neuron markers such as NEFL,
GABRA1, SYT1, and SLC12A5.
Standard Therapy for Glioblastoma
Standard therapy for patients with newly diagnosed GB
includes maximal, safe surgical resection and then concurrent
radiotherapy (RT) and temozolomide (TMZ) followed by adju-
vant TMZ for 6 or more cycles. This treatment leads to a median
survival for GB of 14 to 15 months. What follows is a brief dis-
cussion of each modality used in upfront treatment.
Surgery
Surgical debulking is the initial therapy of choice for GB and
may lead to rapid improvement of symptoms by alleviating
mass effect from the tumor. However, because of GB’s infiltrative
growth pattern, residual tumor cells persist despite a macro-
scopically “total” resection. Of course, surgical resection is also
critical for pathologic diagnosis. Tissue obtained at the time of
resection likewise affords individualized analysis of the tumor’s
molecular signature, which may be needed for clinical trials
requiring study of molecular markers in conjunction with the
targeted therapies discussed later in this article.
Technologic advances have improved the safety and the extent
of surgical resection. Yet, tumor localization in eloquent areas
(eg, primary motor or speech cortex) or infiltration of the corpus
callosum may allow for only a partial resection. State-of-the-art
planning of a tumor resection involves multimodal imaging
including conventional and functional MRI (fMRI), diffusion
tensor imaging (DTI), and magnetic source imaging (MSI)
sequences to visualize functional brain areas and fiber tracts.
fMRI uses cortical blood flow fluctuations as a surrogate for
increased or decreased brain activity, widely being used to map
task-driven regional cortical activity in patients. For example,
resection of tumors in or encroaching on motor cortex is often
limited by risk of postoperative paresis. The delineation between
tumor and sensorimotor cortex is important in limiting this risk
and is traditionally performed intraoperatively by electrophysi-
ologic mapping. The combination of preoperative fMRI and intra-
operative monitoring leads to more efficient mapping of cortical
function during resection compared with neuromonitoring alone.
3
Several studies have demonstrated the utility of DTI with
regard to intraoperative functional mapping and preservation
of neurologic function after surgical resection. DTI is based on
the principle that water preferentially diffuses along the long
axis of white matter tracts and is used to delineate white matter
anatomy. In a process called tractography, DTI can be processed
to reconstruct 3-dimensional constructs representing subcortical
fiber tracts, thereby mapping alterations of white matter archi-
tecture secondary to a tumor or edema surrounding a tumor,
providing guidance during surgical resection.
Magnetoencephalography (MEG) is the study of evoked (ie,
sensory, motor, or cognitive) magnetic signals generated by
intracellular electric current flow in the brain, making it a direct
recording of aggregated neuronal activity. MSI is the coregis-
tration of these evoked magnetic fields with high-resolution
brain MRI to enable anatomic localization of the MEG record-
ings. This mapping of cortical functional organization can be
used in the preoperative mapping of brain function. MSI allows
the tracking of neuronal activity on a scale of milliseconds with
millimeter accuracy and is thus a viable noninvasive alternative
to the Wada test in the presurgical determination of language
lateralization.
Intraoperative monitoring along with cortical and subcortical
stimulation similarly reduces the risk of permanent deficits.
Preoperative imaging is a valuable tool for surgical planning.
However, “brain shift” from changes in tumor volume, cere-
brospinal fluid (CSF) drainage, intracranial pressure, or the
use of brain retractors can make preoperative neuronavigation
information inaccurate. Intraoperative MRI revises the navi-
gational image as necessary and has become a valuable tool
to maximize surgical resection.
Observational studies robustly suggest that maximal sur-
gical resection improves patient survival independent of age
and Karnofsky performance scale score. However, there has
never been a controlled, randomized trial to assess whether
partial resection of tumors is as effective as maximal resection.
Markers for the intraoperative detection and resection of
tumors have been used in an effort to enhance the extent of
resection of high-grade gliomas and maximize probable sur-
vival benefits of surgery. An example is the oral administration
of a nonfluorescent prodrug, 5-aminolevulinic acid (5-ALA),
which is metabolized to fluorescent protoporphyrin IX (PpIX)
in tumor tissue through the heme biosynthesis pathway. PpIX
accumulation in high-grade glioma ensues because 5-ALA
uptake into the tumor tissue is increased through a disrupted
blood–brain barrier, increased neovascularization, and the
overexpression of membrane transporters in glioma tissue.
ALA-induced PpIX in normal brain tissue is relatively low,
allowing for tumor-to-normal tissue contrast.
The use of an operative microscope adapted for visual-
ization of the fluorescent PpIX with blue light allows the sur-
geon to visualize the tumor as red in color. Minimal adverse
effects have been reported with ALA, including skin photo-
sensitivity. A phase III trial using 5-ALA resulted in a 65%
rate of complete resection, compared with 35% for conven-
tional surgical techniques. Regardless of other treatment
modalities used in this trial, gross total resection provided a
survival advantage. Limitations in use of 5-ALA during sur-
gical resection include the depth of penetration of blue light
to a few millimeters and it can be obscured by blood products.
In addition, nonenhancing tumors do not fluoresce well.
Another limitation to 5-ALA use is a “photobleaching effect,”
meaning that under light exposure, like that of operating
room lights and the operative microscope, the intensity of
PpIX fluorescence wanes.
Minimally invasive neuroendoscopic procedures have also
advanced the resection of tumors. They involve use of a fiber-
optic lens endoscope to navigate the CSF-filled ventricular
cavities in the brain as a channel for access to tumor biopsy or
resection. The technique has supplemented older neurosurgical
strategies and is also used to perform third ventriculostomy
for the relief of obstructive hydrocephalus caused by a tumor.
Neuronavigation technology confirms the location of the endo-
scope with MRI of the brain. Neuroendoscopic techniques can
be used to resect not only intraventricular tumors but also,
because of the trajectory from the ventricular cavities, tumors
in eloquent midline areas of the brain.
Radiotherapy
RT has been the foundation of treatment in patients with
high-grade glioma for decades. Postoperative RT improves
survival in patients with GB from a range of 3 to 4 months to
a range of 7 to 12 months. Although the type of radiation has
not changed, the ability to focus it and tailor it to the irregular
borders of brain tumors and minimize the dose to nearby crit-
ical structures with intensity-modulated or image-guided tech-
niques has improved. Fractionated external-beam RT (EBRT)
is the standard of care for patients with GB, given as 60 Gy of
conformal EBRT delivered 5 days per week in 1.8- to 2.0-Gy
fractions to a 2-cm margin. Intensity-modulated RT may result
in less radiation delivered to normal tissues and is likely to be
comparable with EBRT, although comparative trials are want-
ing. Other techniques combined with conventional RT, includ-
ing brachytherapy, hyperfractionation, and stereotactic
radiosurgery, have not improved survival in GB patients
Another reason modern techniques allow for better sparing
of surrounding normal structures/tissues while maintaining
high dose to the defined treatment area is that MRI is now
used to define tumor volume within the brain. Target volumes
used to be defined on a planning CT scan, but treatment plan-
ning software can register, or fuse, MRI and CT scans, with
the MRI scan serving as a guide for defining the treatment
volume.
Chemotherapy
Before 2005, cytotoxic chemotherapy had a minor role in GB
therapy because of the perceived marginal efficacy of adjuvant
chemotherapy in early studies. Large meta-analyses were
needed to reveal a modest benefit in the use of chemotherapy
for patients with high-grade gliomas. Generally, patients were
treated with nitrosourea-based chemotherapeutic regimens,
which demonstrated a modest survival benefit at 1 year of
approximately 6% to 10%. In 2005, a phase III trial in patients
with newly diagnosed GB compared standard RT alone versus
RT in combination with TMZ. Patients in the combination arm
were also subsequently treated with adjuvant TMZ 6 cycles.
This combination was well tolerated and increased the median
survival from 12.1 to 14.6 months versus RT alone. The per-
centage of 2-year survivors also increased to 26.5% in the com-
bination group versus 10.4% with RT. Because of this trial,
4
maximal surgical resection followed by radiation with concur-
rent and adjuvant TMZ is now the standard of care for patients
with newly diagnosed glioblastoma multiforme (GBM).
TMZ is an alkylating agent, which adds a methyl group to
the O6, N3, and N7 positions of guanine on DNA, resulting in
futile cycling of the mismatch repair system in tumor cells,
ultimately inducing apoptosis. Resistance to alkylating agents
is mediated by the DNA repair enzyme O6-methylguanine
methyltransferase (MGMT). Hypermethylation of the promoter
region of the MGMT gene results in loss of MGMT function.
MGMT promoter methylation status is associated with survival
in patients with newly diagnosed GBM who are treated with
RT and TMZ. The 2- and 5-year survival rates for GBM patients
treated with TMZ in the earlier-mentioned trial were 49% and
14% for patients with a methylated MGMT promoter, com-
pared with 15% and 8% for patients with an unmethylated
MGMT promoter. Pseudoprogression, defined as a radiologic
pattern suggesting progression after RT with concurrent TMZ,
is seen more often in patients with a methylated MGMT pro-
moter. It also thought that MGMT promoter methylation may
be associated with an increased incidence of distant tumor
recurrences after standard treatment with RT and TMZ.
Research on how to overcome MGMT-mediated resistance
to TMZ is ongoing. As TMZ is an MGMT substrate, it was
thought that dose-intense TMZ regimens (higher and/or more
prolonged doses of TMZ) could improve outcomes for GB
patients. It was hypothesized that in patients with methylated
MGMT, more TMZ could enhance cytotoxicity, whereas in those
patients not hypermethylated, more TMZ could overcome drug
resistance by overwhelming or depleting the MGMT. A random-
ized phase III trial in newly diagnosed GB, comparing dose
intense TMZ versus the standard 5-day regimen has recently
been completed by the Radiation Therapy Oncology Group but
results did not show a benefit for the dose-dense group. Other
alkylators, such as lomustine (CCNU), also deplete MGMT and
in small prospective studies, CCNU was combined with TMZ
after standard RT. Although hematologic toxicity was increased,
the median overall survival was 23.1 months, suggesting possible
synergy in MGMT depletion. Whether combination alkylator
chemotherapy to overcome MGMT-mediated resistance will
improve overall survival and have an acceptable toxicity profile
may warrant further study. Either way, discovering alternative
treatment approaches for patients with an unmethylated MGMT
promoter is an important challenge to overcome.
Recent phase II trials in newly diagnosed GBM focused on
the addition of novel agents to radiation and TMZ, being
dubbed “Temodar plus trials.” A number of agents were used
in these trials, examples of which include erlotinib, enzastaurin,
talampanel, poly-ICLC, and cilengitide. Close scrutiny of these
Temodar plus trials reveals relative similarities with regard
to patient characteristics, eligibility requirements, and imaging
standards. In addition, they demonstrate a trend toward longer
survival compared with patients treated with only TMZ plus
RT. Several TMZ plus RT trials resulted in improved survival
nearing a median of 20 months or beyond. The survival dif-
ferences observed between the more current trials and the
2005 historical control may result from the novel agents them-
selves but could also be due to changing patterns of care for
GB. Until these differences in survival outcomes are further
clarified, comparisons of these phase II studies should be
interpreted with caution because it is unclear whether the
novel agent or the improved care of patients with GB has led
to this trend or whether treatments at progression such as
bevacizumab/clinical trials have influenced results. Of course,
many of the phase II studies suffered from being single-arm
trials limited by the nature of their design. New studies may
need to use randomized phase II designs with an experimental
treatment arm versus a standard RT/TMZ arm. Currently,
small-molecule, targeted agents have not been incorporated
into day-to-day clinical practice in patients with newly diag-
nosed GB. Combination approaches that target multiple path-
ways are still being developed and studied.
Another approach to delivering chemotherapy involves
implanting biodegradable wafers containing carmustime
(BCNU; Gliadel wafers) into the tumor resection cavity. A ran-
domized, placebo-controlled trial yielded a survival benefit of
13.9 months (Gliadel) versus 11.6 months (placebo) in patients
with newly diagnosed GB; however, more recent retrospective
studies of patients treated with implanted BCNU wafers plus
RT with concurrent and adjuvant TMZ have yielded mixed
results. Gliadel may also be associated with more frequent
episodes of wound infection, cerebral edema, and wound break-
down in patients compared with individuals not receiving this
treatment.
Therapy at Progression
Nearly all GBs eventually progress. The median time to pro-
gression for GB is approximately 7 months. Progressive disease
is usually discovered on surveillance imaging, although at times
it is indicated by clinical decline. Progressive disease must be
differentiated from radiation necrosis, postsurgical effects, and
effects of increasing or decreasing steroids. Response Assessment
in Neuro-Oncology (RANO) is a recent proposal that offers
guidelines by which to define progressive or recurrent high-
grade glioma. An important consideration is differentiating
pseudoprogression, imaging changes seen soon after the com-
bination of radiation and TMZ, from true tumor progression.
Pseudoprogression has been reported to occur in more than
30% of patients with GB after chemoradiation and may be more
common in those patients with methylated MGMT status, sug-
gesting that this radiographic pattern may be due to the effects
of therapy. Excluding patients with pseudoprogression from
clinical trials for recurrent high-grade glioma is essential to pre-
vent biased trial results. Yet, it is important to note that no imaging
modality can dependably distinguish pseudoprogression from
true progression, although techniques like MR perfusion, MR
spectroscopy, and positron emission tomography are being
investigated. Ultimately, tissue acquisition may be needed in
some cases.
Once progression of a tumor occurs, treatment options include
repeat surgical resection, radiation, chemotherapy with standard
agents, novel therapies, or a combination of these. What follows
is a brief discussion of each of these choices with chemotherapy
broken down into a number of sections.
Repeat Surgery
There are various reports on the reoperation of recurrent
GB. In approximately 85% of cases, tumor recurs locally mak-
ing reoperation feasible. The rate of reoperation ranges from
5
10% to 33% depending on the center. Surgery may be con-
sidered a method by which to treat progressive disease and
to confirm pathology or differentiate progression from
pseudoprogression. In selected patients, surgery may also
reduce symptoms and improve quality of life. Recent studies
demonstrate that progression-free survival (PFS) at 6 months
and overall survival results for patients with and without
surgical intervention at the time of progression are similar,
allowing data from these patients to be combined in assessing
the benefit of new treatments without the need for stratifi-
cation or other statistical adjustment.
One of the major challenges of chemotherapeutic treatment
of GBM is the achievement of adequate drug concentration
within the tumor itself. The blood–brain barrier, though often
impaired in areas of bulky tumor, still acts as a barrier against
many drugs, particularly in the periphery of the tumor, which
is often highly infiltrative. Therefore, a variety of alternative sur-
gical delivery methods have been evaluated. Convection-
enhanced delivery (CED) is one such strategy for local drug
delivery. The technique involves the placement of several
catheters into a surgical cavity immediately after resection; anti-
neoplastic agents are then delivered through the catheters using
convection, which improves distribution within the surrounding
tissue where residual tumor cells persist. Early phase studies
using CED to deliver an assortment of agents in patients with
recurrent malignant gliomas have been promising, although
neither it nor any other agent administered via this technique
has received approval.
Re-Irradiation
Patients with recurrent GB almost invariably underwent
a previous full course of EBRT, making re-irradiation or radio-
surgery more difficult and potentially more toxic. Moreover,
though trials are lacking, there is a significant risk that re-
irradiation may lead to radiation necrosis and neurologic
compromise.
Clinical trials in GB of brachytherapy, hyperfractionation,
and stereotactic radiosurgery have not demonstrated con-
sistently improved survival in recurrent high-grade glioma.
Radiosurgery, which is highly focused radiation, is generally
given with a Gamma knife, Cyber knife, or specially adapted
linear accelerator. Gamma knife radiosurgery is given as a
single fraction, whereas Cyber knife or linear accelerator-
based radiosurgery may be fractionated. In the brain, radio-
surgery tends to be used for lesions up to about 4 cm in
maximum diameter. The radiation necrosis rate seems to be
lower after fractionated radiosurgery than after single-fraction
radiosurgery.
Given the difficulty and risk of toxicity of brain re-irradi-
ation and or radiosurgery, it is offered to a relatively small
minority of patients with recurrent GB. These techniques
tend to be administered at centers with aggressive treatment
philosophies, in highly selected patients with somewhat focal
disease and good performance status. It is appropriate that
salvage therapy be highly individualized, but the obvious
selection bias makes it difficult to make conclusions regarding
the benefit of re-irradiation or radiosurgery. In addition, both
local failure and symptomatic radiation necrosis are common
after re-irradiation. Interestingly, there are several reports of
bevacizumab being used to manage cerebral radiation
necrosis successfully and clinical trials in development that
combine re-irradiation strategies with bevacizumab.
Rather than to use radiation at recurrence, current focus is
on the addition of systemic radiation-sensitizing agents and
optimization of target delineation to improve the therapeutic
ratio of RT. Although initial studies using radiosensitizers were
unsuccessful, the results reported in conjunction with TMZ
establish a precedent that radiosensitization may improve out-
come. The role of proton beam RT is another area of possible
benefit if availability can be broadened and the cost reduced.
Further improvements in neuroimaging also will allow us to
tailor therapy more precisely for each individual patient.
Temozolomide
Similar to the newly diagnosed population mentioned ear-
lier, a variety of schedules of dose-dense TMZ in recurrent GB
have been studied and most compare favorably with outcomes
of other chemotherapeutic agents used in recurrent GB.
Another mechanism of resistance to TMZ is mediated through
the base excision repair system, of which poly (adenosine-
diphosphate-ribose) polymerase (PARP) is a component. PARP
inhibitors may enhance TMZ-induced cytotoxicity and con-
tinue in early-phase clinical trials in combination with TMZ.
Targeted Agents and Biomarkers
As detailed earlier, significant advancement has been made
in our understanding of the molecular pathogenesis and sig-
naling pathways that drive GB formation. Agents targeting
cell surface growth factor receptors, such as PDGFR, EGFR,
and VEGFR, and intracellular signaling pathways, such as
the PI3K/Akt pathway, have been tested in patients with GB.
Nevertheless, most did not result in radiographic response
or prolongation of survival, chiefly because of poor
blood–brain barrier penetration and redundancy of intracel-
lular signaling pathways. Because of the difficulty of obtaining
tumor tissue from a patient with a brain tumor, few clinical
trials measure drug levels in tumor tissue. However, recently
initiated early phase studies, through such mechanisms as
the Ivy Foundation, are designed to obtain and study tumor
tissue in terms of drug penetration, degree of target inhibition
in vivo, and resistance mechanisms. This information increases
the efficiency of clinical testing and may influence the design
of future trials.
In a further effort to improve on these disappointing results,
ongoing clinical trials combine novel therapies that inhibit
multiple targets or multiple agents that inhibit complementary
pathways. Furthermore, some of these trials combine novel
agents with radiation and cytotoxic chemotherapy or with
other targeted therapies. A challenge to combination therapy
is additive toxicity, which may limit therapeutic doses.
Another explanation for the failure of targeted drugs is
that the targets critical for effective therapies have not been
targeted. Alternative promising therapeutic targets in devel-
opment are MET, fibroblast growth factor receptor, heat shock
protein–90, HIF1␣, and cyclin-dependent kinases. In addition
to the ambiguity of which targets to inhibit, there is an ongoing
debate on which cell types may require targeting. For example,
glioma stem cells may initiate glioma formation and maintain
the tumor mass. As such, inhibition of stem cell targets such
6
as Notch and Sonic hedgehog may overcome resistance to
treatment.
Perhaps, results will also improve with the identification
of biomarkers that predict response to therapy including to
novel agents. These efforts continue but thus far have yielded
inconsistent results. Proteomics may further our understanding
of tumor biology and help us to identify better treatment
agents. Proteomic analysis of high-grade glioma has been lim-
ited because previous technologies could not reflect real-time
analyses and thus translation to the clinical setting was impos-
sible. However, high-throughput proteomic methods are now
available and may be used as an efficient and cost-effective
way to detect proteins, which will accelerate the understanding
of tumor biology, the discovery of biomarkers, and ultimately
the innovation of more effective therapies.
To date, the presence of individual biomarkers like insulin-
like growth factor binding protein 2, transforming growth fac-
tor–␤1/2, and VEGF, and endothelial progenitor cells in the
plasma or serum of GB patients, have been correlated with
patient outcome and demonstrate that the tumor can elicit sys-
temic responses, warranting further proteomic investigation.
Studies are also using CSF as a source of biomarkers. It is hoped
that measuring alterations in the protein composition of CSF
can be a sensitive indicator of tumor biology and permit the
design of biomarker panels that can be used in clinical trials
oriented toward a personalized treatment for a specific patient.
Immunotherapy
The genesis of cancer and immunosuppression are indu-
bitably related. Under ideal circumstances, immune surveillance
identifies neoplastic cells and subsequently destroys them.
However, tumor cells manage to avoid detection by the immune
system and the cancer cells that avoid surveillance are able to
proliferate and acquire additional immunoevasive mechanisms.
As such, by the time the tumor is clinically apparent it is adept
at avoiding the immune system in a variety ways.
The brain is an immune-privileged site, being shielded from
some immunoglobulins and circulating leukocytes but immuno-
surveillance does occur and may result in tumor elimination or
tumor escape. Clearly, GB overcome the immune system and
likely co-opt the leukocyte populations that invade them. For
example, GB is believed to release factors that in turn recruit
bone marrow progenitor cells that support angiogenesis. Tumor-
infiltrating monocytes and macrophages into GB release proan-
giogenic factors, including VEGF. In addition, myeloid suppressor
cells that infiltrate gliomas inhibit dendritic cell (DC) maturation
and antitumor talents of T cells and natural killer cells.
On the basis of this understanding, many immunologic
approaches have been studied in treating gliomas. An example
is using T cell–mediated action against GB, via adoptive immune
transfer, which involves the transfer of effector T cells after an
in vitro priming process against a tumor antigen. This approach
is feasible in animal models, and has been used in early-phase
clinical trials. Such studies to date have focused on eliciting an
antitumor response in vivo, through injection of antigen (active
immunotherapy or tumor vaccination) or by using DC-based
vaccines, in which DCs are pulsed with antigen in vitro and
implanted intradermally in vivo to stimulate an immune
response. Phase 1 trials are currently ongoing in which patients
receive autologous DCs that are pulsed with their own tumor
antigens. If successful, these strategies could lead to personalized
immunotherapy, in which the patient’s own immune system
is boosted to produce antitumor immune responses.
Several immunostimulant approaches have been studied in
the treatment of GB. The advent of recombinant DNA technology
led to a nonspecific immune strategy via administration of
cytokines or immune biologic modifiers. These agents were
administered systemically with the hope that they would boost
the immune response in patients with brain tumors. Most sys-
temic treatments have been met with only modest results and
a high degree of toxicity. Local injection of cytokines has also
led to mixed results and adverse effects. In trying to mimic their
natural activity more closely, cytokines recently have been deliv-
ered either by implanting genetically transduced cells or by
using in vivo gene transfer techniques. Although effective in
animal models, these strategies either have not moved into
human clinical trials or have failed to eradicate gliomas. Another
immunotherapeutic approach is the delivery of antibodies, typ-
ically a cytotoxin-conjugated or radioactively armed antibody
against a known glioma antigen. Clinical trials are ongoing
using such antibodies against cell surface antigens including
EGFRvIII, EphA2 receptor, IL–13R␣2, and others.
Combining more than one mode of immunotherapy may
provide better results. For example, peptide vaccinations may
be used in conjunction with a cytokine adjuvant to produce
more widespread immune response. Pursuits continue to tease
out the optimal mix of interferons, cytokines, chemokines, and
others, for responding to particular pathogens, such that we
can begin to harness these systems for our benefit. Advances
must also be made in understanding how to overcome the
immunologic privilege of the central nervous system and the
immunosuppression of gliomas by combining immunostim-
ulants with other forms of immunotherapy like passive
antibody treatment, active immunotherapy, or adoptive
immunotherapy strategies.
Gene Therapy
Gene therapy is based on the insertion or modification of
genes into a cell to treat a disease. Gene delivery can be accom-
plished using a variety of vectors, from viruses to cell-based sys-
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7
tems to synthetic vectors. In gliomas, viral vectors have been
used to deliver suicide genes, proapoptotic genes, p53, cytokines,
and caspases. Such studies have shown promising preclinical
results, but clinical trials have been limited by the fact that trans-
duced cells were found only within a short distance from the
delivery site. Synthetic vector research has focused on the use of
nanoparticles. Liposomal vectors, for example, have been used
to deliver therapeutic genes in the preclinical setting. At the
current time, this area of research is only starting to blossom.
Further therapy options, including anti-angiogenic therapy, will
be discussed in part III.
After reading this article, the neurosurgeon should be able to
discuss the following items: 1) theories of gliomagenesis; 2) sub-
types of glioblastoma; 3) standard treatment for glioblastoma;
4) how technical and imaging advances have influenced the
resection of glioblastoma; and 5) treatment paradigms for recur-
rent glioblastoma.
Readings
Brem SS, Bierman PJ, Brem H, et al. Central nervous system cancers. J Natl
Compr Canc Netw. 2011;9:352-400.
Chamberlain MC. Emerging clinical principles on the use of bevacizumab
for the treatment of malignant gliomas. Cancer. 116:3988-3999.
Chan MD, Tatter SB, Lesser G, et al. Radiation oncology in brain tumors: cur-
rent approaches and clinical trials in progress. Neuroimaging Clin N Am.
20:401-408.
Chang SM, Nelson S, Vandenberg S, et al. Integration of preoperative anatomic
and metabolic physiologic imaging of newly diagnosed glioma. J Neu-
rooncol. 2009;92:401-415.
Gilbert MR, Wang M, Aldape KD, et al. RTOG 0525: A randomized phase III
trial comparing standard adjuvant temozolomide (TMZ) with a dose-
dense (dd) schedule in newly diagnosed glioblastoma (GBM). J Clin Oncol.
2011;29(May 20 Supplement):abstract 2006.
Holdhoff M, Grossman SA. Controversies in the adjuvant therapy of high-
grade gliomas. Oncologist. 16:351-358.
Nicholas MK, Lukas RV, Chmura S, et al. Molecular heterogeneity in glioblas-
toma: therapeutic opportunities and challenges. Semin Oncol. 38:243-253.
Quant EC, Wen PY. Response assessment in neuro-oncology. Curr Oncol Rep.
13:50-56.
Reardon DA, Galanis E, DeGroot JF, et al. Clinical trial end points for high-
grade glioma: the evolving landscape. Neuro Oncol. 13:353-361.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and
adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.
Wen PY, Brandes AA. Treatment of recurrent high-grade gliomas. Curr Opin
Neurol. 2009;22:657-664.
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1. Recent evidence suggests that cells, called cancer propagat- 6. Clinical trials of radiation and temodar plus an experimental
ing cells or cancer stem cells, promote or produce high-grade agent have indicated that median survival for patients with
gliomas. glioblastoma may be greater than 20 months.
True or False? True or False?
2. Glioblastomas are subdivided into primary and secondary 7. Several imaging modalities like MR perfusion, MR spec-
types based on their molecular profile. troscopy, and positron emission tomography can dependably
distinguish pseudoprogression from true progression.
True or False?
True or False?
3. With regard to surgical resection of high-grade glioma, intra-
operative monitoring, along with cortical and subcortical stim- 8. To date, proteomic analysis of high-grade glioma has been very
ulation, does not reduce the risk of permanent deficits. helpful in determining which therapy is best at tumor recurrence.
True or False? True or False?
4. Observational studies of patients with high-grade glioblastoma 9. The brain is an immune-privileged site, being shielded from
robustly suggest that maximal surgical resection does not some immunoglobulins and circulating leukocytes, but immune
improve patient survival independent of age and Karnofsky surveillance does occur and may result in tumor elimination
performance scale score. or tumor escape.
True or False? True or False?
5. Postoperative radiation improves survival in patients with GB 10. Biomarkers that predict response to therapy, including to novel
from a range of 3 to 4 months to a range of 7 to 12 months. agents, are very useful in predicting high-grade glioma response
to treatment.
True or False?
True or False?