Handbook of Clinical Neurology, Vol.

134 (3rd series)

Gliomas
M.S. Berger and M. Weller, Editors
© 2016 Elsevier B.V. All rights reserved

Chapter 23

Glioblastoma
HANS-GEORG WIRSCHING1*, EVANTHIA GALANIS2, AND MICHAEL WELLER1
1
Department of Neurology, University Hospital Zurich, Zurich, Switzerland
2
Departments of Oncology and Molecular Medicine, Mayo Clinic, Rochester, MN, USA

Abstract
Glioblastoma is the most common and aggressive primary brain tumor in adults. Defining histopathologic
features are necrosis and endothelial proliferation, resulting in the assignment of grade IV, the highest
grade in the World Health Organization (WHO) classification of brain tumors. The classic clinical term
“secondary glioblastoma” refers to a minority of glioblastomas that evolve from previously diagnosed
WHO grade II or grade III gliomas. Specific point mutations of the genes encoding isocitrate dehydro-
genase (IDH) 1 or 2 appear to define molecularly these tumors that are associated with younger age and
more favorable outcome; the vast majority of glioblastomas are IDH wild-type. Typical molecular
changes in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sar-
coma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signaling. Standard
treatment of glioblastoma includes surgery, radiotherapy, and alkylating chemotherapy. Promoter meth-
ylation of the gene encoding the DNA repair protein, O6-methylguanyl DNA methyltransferase (MGMT),
predicts benefit from alkylating chemotherapy with temozolomide and guides choice of first-line treat-
ment in elderly patients. Current developments focus on targeting the molecular characteristics that drive
the malignant phenotype, including altered signal transduction and angiogenesis, and more recently,
various approaches of immunotherapy.

EPIDEMIOLOGY AND Risk factors

PATHOPHYSIOLOGY
Glioblastoma is a disease that accounts for 45.6% of pri-
mary malignant brain tumors, yet the annual incidence
of 3.1 per 100 000 is low compared to cancers arising
from other organs such as breast (171.20 per 100 000)
or prostate (201.40 per 100 000: Ostrom et al., 2014a).
The annual age-adjusted incidence of glioblastoma
increases with age from 0.15 per 100 000 in children to
the peak of 15.03 per 100 000 in patients aged 75–84 years
(Ostrom et al., 2014a). Survival is inversely associated
with age: 5% of all patients diagnosed with glioblastoma
are alive after 5 years, and this measure decreases to 2%
among patients aged 65 years or older (Ostrom
et al., 2014a).
Risk factors for the development of glioblastoma other
than age are poorly defined (Weller et al., 2015a). Males
are affected more often than females (1.6:1) and whites
more often than blacks (2:1) (Ostrom et al., 2014a).
Causes of these asymmetric distributions are elusive.
A small subset of less than 1% of glioblastomas are asso-
ciated with hereditary cancer syndromes, including neu-
rofibromatosis types 1 and 2, Turcot syndrome and Li–
Fraumeni syndrome, usually secondary to the diagnosis
of World Health Organization (WHO) grade II or III gli-
omas (Ohgaki et al., 2010). A population-based study
including 10 834 patients treated with low-dose radio-
therapy of the scalp for tinea capitis of 1–6 Gy in the
1950s confirmed a relative risk (RR) increase for

*Correspondence to: Hans-Georg Wirsching, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26,
CH-8091 Zurich, Switzerland. Tel: +41-44-255-5500, Fax: +41-44-255-4507, E-mail: hans-georg.wirsching@usz.ch
382 H-G. WIRSCHING ET AL.
gliomas of 2.6 (95% confidence interval (CI), 0.8–8.6),
and the excess RR for malignant tumors followed linear
kinetics and was 1.98/Gy (95% CI, 0.73–4.69) (Ron et al.,
1988; Sadetzki et al., 2005). Among long-term survivors
who underwent high-dose irradiation (30–44.9 Gy) for
primary brain tumors in childhood, the odds ratio was
21 for gliomas (n ¼ 40, including n ¼ 9 glioblastomas)
and the excess RR/Gy was 0.33 (95% CI, 0.07–1.71)
(Neglia et al., 2006). The radiation dose of diagnostic
scans does not suffice as a risk factor (Brada et al.,
1992; Minniti et al., 2005). Mobile phone use has been
studied extensively with respect to gliomagenesis, but
no definite association has been reported (Interphone
Study Group, 2010; Ostrom et al., 2014b). No association
with smoking or other cancerogenic agents has been
reported. Expression of cytomegalovirus (CMV) genes
and interaction of CMV gene products with some of
the core pathways that drive the malignant phenotype
of glioblastoma suggest an oncomodulatory role for
CMV, but a firm role for CMV as a glioma-initiating
agent remains to be confirmed (Dziurzynski et al.,
2012; Wick and Platten, 2014). In summary, ionizing irra-
diation of the brain is the only recognized exogenous risk
factor for the development of glioblastoma (Connelly
and Malkin, 2007; Bondy et al., 2008; Ostrom and
Barnholtz-Sloan, 2011).
Cell of origin
The low frequency of glioblastoma and of primary brain
tumors in general compared to tumors arising from
extraneural organs may reflect a high degree of protec-
tion of the brain from genotoxic stress. ATP-binding cas-
sette (ABC) family transporter molecules of the blood–
brain barrier restrict diffusion of chemical mutagens to
the brain (El Ali and Hermann, 2011). Furthermore, DNA
is particularly sensitive to genotoxic stress during repli-
cation, but most brain cells have entered a definite post-
mitotic state until adulthood. Experimental data suggest
that adult glioblastoma may be derived from the small
pool of adult neural stem and progenitor cells (NSPC),
which are located in the subventricular zone (Sanai
et al., 2004), the subcortical white matter (Nunes et al.,
2003), and the dentate gyrus of the hippocampus
(Eriksson et al., 1998). NSPC have retained the ability
to enter mitosis and play a major role for the plasticity
of the brain in learning and memory (Sanai et al.,
2005). A subpopulation of glioblastoma cells termed
glioma-initiating (also called glioma stem-like cells)
share various features with NSPC, including the location
in perivascular and hypoxic niches (Gilbertson and Rich,
2007), self-renewal (i.e., the capability to divide into two
progeny, of which at least one resembles the initial cell)
and multilineage differentiation (i.e., the capability to
divide into different, more differentiated cell types).
Finally, the capability to form secondary tumors in serial
xenotransplantation assays that resemble the original
tumors is a defining criterion of glioma-initiating cells.
Various markers of glioma-initiating cells have been
described, including CD133 (prominin) (Singh et al.,
2004), CD15 (stage-specific embryonic antigen-1) (Son
et al., 2009), CD44 (Pietras et al., 2014), and integrin
alpha 6 (Lathia et al., 2010) but the abundance of any
of these markers differs strongly between tumors
(Yan et al., 2013). Most progeny of glioma-initiating cells
have features of astrocytes, but differentiation into
functional endothelial cells and pericytes has been noted,
too (Ricci-Vitiani et al., 2010; Wang et al., 2010; Cheng
et al., 2013). Glioma-initiating cells have been attributed
a crucial role in growth, angiogenesis, invasion, and
resistance to radiotherapy (Bao et al., 2006) and chemo-
therapy (Beier et al., 2008; Chen et al., 2012), but, despite
promising preclinical data, no drugs specifically target-
ing glioma-initiating cells have entered clinical practice
to date.
Tumor location
There is no association of the location of glioblastoma at
diagnosis with the locations of NSPC, besides the con-
finement of most glioblastomas to the supratentorial
compartment. Reasons likely include excessive dissemi-
nation of glioblastoma cells throughout the brain even at
early stages of the disease, but development of glioblas-
toma from non-NSPC cannot be excluded. Most gliomas
occur in the frontal (25.8%), temporal (19.7%), and pari-
etal (12.2%) lobes, whereas occipital-lobe (3.2%), cere-
bellar (2.9%), brainstem (4.2%), or spinal cord (4.3%)
gliomas are relatively rare (Ostrom et al., 2014a). Brain-
stem gliomas are rare in adults, but account for the vast
majority of pediatric glioblastomas (Ostrom et al., 2015).
Survival of patients with frontal-lobe glioblastomas was
longer compared to patients with temporal- or parietal-
lobe glioblastoma (median overall survival (OS), 11.4
vs. 9.1 vs. 9.6 months, log rank p ¼ 0.01) in a cohort of
645 adults who were treated within three consecutive tri-
als of the Radiation Therapy Oncology Group (RTOG) in
the pre-temozolomide era (Simpson et al., 1993). This is
likely due to an association of frontal-lobe glioblastoma
with other favorable prognostic features, such as youn-
ger age, isocitrate dehydrogenase-1/2 (IDH-1/2) muta-
tions (Sturm et al., 2012; Ellingson et al., 2013), and
higher rates of gross total resection (Lacroix et al.,
2001). Approximately half of all glioblastomas in adults
infiltrate more than one lobe and approximately 5%
grow multifocally (Djalilian et al., 1999). Leptomenin-
geal dissemination of glioblastoma cells is rare and
occurs in late stages of the disease (Herrlinger et al.,
 GLIOBLASTOMA
2004), although a frequency of up to 14% has been
reported in one series comprising younger patients
(median age, 31 years) (Arita et al., 1994). In another
series, 5 of 25 autopsied patients with glioblastoma
had spinal leptomeningeal metastases (Erlich and
Davis, 1978). Associations of leptomeningeal dissemina-
tion with younger age, male gender, incomplete tumor
removal, multiple resections, ventricular entry or prox-
imity of the tumor to the ventricular system, and with
gains at the 1p36 chromosomal region, have been noted
(Awad et al., 1986; Grabb et al., 1992; Arita et al., 1994;
Lindsay et al., 2002; Korshunov et al., 2007). Distant
organ metastases arising from glioblastoma have been
reported, predominantly to lung, pleura, lymph nodes,
bone, and liver (Schweitzer et al., 2001), but these cases
are rare. The reasons for the strong brain tropism of glio-
blastoma cells are not known, but likely include adapta-
tion to the metabolic and immunologic peculiarities of
the brain microenvironment that precludes survival in
other organs (Fecci et al., 2014; Mashimo et al., 2014).
Furthermore, spreading glioblastoma cells reactivate
developmental programs of neuroglial precursor cells
and may follow the same paths along which neuroglial
precursor cells migrate during development, and extra-
neural migration of neuroglial precursor cells does not
occur. Due to the restriction of glioblastoma cell spread-
ing within the borders of the central nervous system, the
transplantation of organs from donors with glioblas-
toma is per se feasible (Watson et al., 2010; Warrens
et al., 2012), but only few glioblastoma patients qualify
as organ donors. This is because the mode of death is
mostly a gradual decline in a home or hospice setting,
whereas organ donation requires brain death due to a
sudden intracranial event (e.g., hemorrhage), or gradual
death from compromised airway protection in a hospi-
tal setting that includes intubation to enable nonheart-
beating donation (Collignon et al., 2004).
Clinical course
The clinical course of glioblastoma is determined by
tumor location and dynamics of spread within the brain.
Tissue destruction, edema, and epilepsy likewise con-
tribute to clinical symptoms, causing rapid deteriora-
tion in some patients. The clinical term secondary
glioblastoma refers to glioblastomas that are preceded
by the histologic diagnosis of WHO grade II or III
gliomas, but this term is increasingly dispensable with
molecular marker-based classifications of gliomas
(Weller et al., 2015a).
Despite the invariably fatal prognosis of glioblas-
toma, any of the standard treatment options discussed
further below may keep stable or even improve quality
of life and cognitive functioning for the time being, even
383
in the particularly impaired elderly population (Roa
et al., 2004; Taphoorn et al., 2005; Keime-Guibert
et al., 2007; Gallego Perez-Larraya et al., 2011). Person-
ality changes and mood disorders commonly occur in
patients with frontal tumors, and these may be mistaken
for psychogenic disorders or part of the physiologic
aging process and thus delay diagnosis. Sensorimotor
deficits are the presenting symptom in approximately
20% of all patients with glioblastoma, and approxi-
mately 5% of patients present with aphasia due to
tumors arising in the speech-dominant hemisphere
(mostly left-sided) (Yuile et al., 2006).
Epilepsy may mimic aphasia or sensorimotor deficits
from tissue destruction postictally and occurs more fre-
quently in glioblastomas that affect the temporal lobe
(Chaichana et al., 2009). Epilepsy is the presenting symp-
tom in 24–68% of glioblastomas and develops in 19–38%
later during the course of the disease (Wick et al., 2005;
Chaichana et al., 2009; van Breemen et al., 2009;
Kerkhof et al., 2013). As a presenting symptom, epilepsy
is associated with longer survival, probably due to an
association with younger age as well as cortical location
and smaller tumor size, indicating good surgical resect-
ability and possibly diagnosis earlier during the disease
course (Yuile et al., 2006; Chaichana et al., 2009). Head-
aches are the presenting symptom in less than one-third
of all patients with glioblastoma (Yuile et al., 2006), and
are mostly dull in nature and typically present at night or
at awakening. Other signs of increased intracranial pres-
sure, such as nausea, vomiting, dizziness, fatigue, and
neurocognitive slowing, occur increasingly during the
disease course, but may be present at diagnosis. Rarely,
leptomeningeal dissemination may mimic painful nerve
root compression, myelitis, and other spinal diseases.
Only few patients retain stable disease and remain neu-
rologically largely asymptomatic for years, but the
majority of patients experience severe impact on quality
of life once first-line treatments have failed (Roa et al.,
2004; Taphoorn et al., 2005; Keime-Guibert et al., 2007;
Gallego Perez-Larraya et al., 2011). In summary, there is
no typical clinical presentation of glioblastoma. Differ-
ences compared to other gliomas include the more rapid
dynamic and somewhat lower incidence of epilepsy (see
Chapter 2).
DIAGNOSIS AND MOLECULAR
CLASSIFICATION
Imaging
New-onset seizures or development of neurologic defi-
cits are commonly followed by a neurologic workup that
includes magnetic resonance imaging (MRI). Computed
tomography (CT) with contrast enhancement is less sen-
sitive in detecting the typical features of glioblastoma.
384 H-G. WIRSCHING ET AL.
Its use is restricted to acute situations, e.g., when hem-
orrhage is suspected, or when MRI is not available or
not possible, e.g., in patients with cardiac pacemakers
or other metallic implants. Prior to biopsies, amino acid
positron emission tomography (PET) is increasingly per-
formed to guide the site of biopsy to metabolic hotspots
that may represent sites of higher tumor grade
(la Fougere et al., 2011); yet, PET is not part of the stan-
dard workup of glioblastoma patients (see Chapter 3).
On MRI, glioblastomas appear as masses with con-
trast enhancement at their margin as a correlate of
blood–brain barrier disruption, central hypointensity on
T2-weighted images as a correlate of necrosis, and perifo-
cal hyperintensity on T2-weighted and fluid-attenuated
inversion recovery (FLAIR) images as a correlate of
edema or noncontrast-enhancing tumor (Fig. 23.1). MR
spectroscopy, T1 contrast subtraction maps, as well as
diffusion/perfusion- and susceptibility-weighted MRI
sequences have refined radiographic diagnostics and
enable more reliable discrimination of glioblastoma from
other contrast-enhancing lesions, including abscesses, pri-
mary central nervous system lymphomas, and metastases

Fig. 23.1. Neuroimaging features of glioblastoma. Magnetic resonance imaging (MRI), T1-weighted (A), gadolinium-enhanced
(B), T2-weighted (C), fluid-attenuated inversion recovery (FLAIR, D); (E): 18F-fluoro-ethyl-tyrosine (FET) positron emission
tomography (PET).
 GLIOBLASTOMA
from nonprimary brain tumors (Kono et al., 2001;
Law et al., 2003; Weber et al., 2006; Ellingson et al.,
2012; Kickingereder et al., 2014), as discussed in more
detail in Chapter 3. However, the appearance of glio-
blastoma on imaging scans can vary considerably, and
therefore tissue-based diagnosis is indispensable (Weller
et al., 2014).
Histopathology
The defining histopathologic features of glioblastoma
are necrosis and microvascular proliferation, and these
qualify glioblastoma for the highest grade in the WHO
classification of primary brain tumors, grade IV
(Louis et al., 2007). Other signs of malignancy that are
present in glioblastoma include anaplasia, high mitotic
rates, and invasiveness, but these features are also pre-
sent in anaplastic gliomas, which are assigned WHO
grade III (Louis et al., 2007). In addition, immunohisto-
chemical markers are commonly assessed to ascertain
the diagnosis of glioblastoma, including glial fibrillary
acidic protein expression to confirm astrocytic lineage
differentiation and MIB-1/Ki-67 to aid quantification
of proliferation. An antibody that specifically detects
mutant IDH-1R132H (Capper et al., 2009) has been inte-
grated into the standard diagnostic workup of suspected
glioblastoma, but it must be recognized that this anti-
body does not detect other IDH-1 or IDH-2 mutations.
A more detailed overview on histopathologic grading
of gliomas is provided in Chapter 5. We emphasize
that the traditional histopathologic definition of glio-
blastoma (and other gliomas) is likely to be comple-
mented by molecular approaches with the next edition
of the WHO classification of brain tumors, due to be
released in 2016.
Glioblastoma variants
Two rare histopathologic variants of glioblastoma are
defined in the WHO classification of primary brain
tumors, gliosarcoma and giant cell glioblastoma (Louis
et al., 2007).
GLIOSARCOMA
Gliosarcoma is characterized by a metaplastic mesenchy-
mal component that stains for reticulin and may show
signs of fibroblastic, cartilaginous, osseous, smooth
and striated muscle, or adipose cell lineage, and these
features are present in addition to characteristics of glio-
blastoma (Han et al., 2010). Gliosarcomas comprise
approximately 2% of all patients diagnosed with glio-
blastoma or gliosarcoma and clinical features include
predilection for location in the temporal lobe, a
meningioma-like macroscopic appearance at surgery,
and frequent reports of extracranial metastases.
385
Development of gliosarcoma may occur secondary to
glioblastoma and molecularly, mutations of the epithe-
lial growth factor receptor (EGFR) are infrequent com-
pared to glioblastoma. The prognosis may or may not be
worse than for glioblastoma, after adjustment for com-
mon prognostic factors (hazard ratio (HR), 1.17; 95%
confidence interval (CI), 1.05–1.31) (Kozak et al., 2009).
GIANT CELL GLIOBLASTOMA
Giant cell glioblastoma is characterized by multinu-
cleated cells with a diameter of more than 500 mm and
lymphocytic infiltration. Giant cell glioblastomas com-
prise approximately 1% of all glioblastomas. The inci-
dence may be higher in young adults (median age at
diagnosis 51 years). The prognosis for patients with giant
cell glioblastoma is better than for glioblastoma, after
adjustment for common prognostic factors (HR, 0.76;
95% CI, 0.59–0.97) (Kozak and Moody, 2009).
Other histopathologic variants have been suggested,
including fibrillary glioblastoma, small cell astrocytoma,
glioblastoma with oligodendroglial component, glioblas-
toma with primitive neuroectodermal tumor, and granu-
lar cell astrocytoma (Karsy et al., 2012), but none of
these have been accepted as designated variants within
the current WHO classification of brain tumors because
of a lack of distinct molecular and clinical features
(Louis et al., 2007).
Molecular markers
MGMT promoter methylation predicts benefit from
temozolomide chemotherapy in newly diagnosed and
probably also recurrent glioblastoma (Hegi et al., 2005;
Malmstrom et al., 2012; Wick et al., 2012; Weller et al.,
2015b). MGMT is a DNA repair protein that counteracts
DNA alkylation by chemotherapy; hypermethylation of
the MGMT promoter results in gene silencing (Weller
et al., 2010). Since the discovery of its role in the resistance
of glioblastoma to alkylating chemotherapy, MGMT has
remained the biomarker with the strongest impact on clin-
ical decision making, particularly in elderly glioblastoma
patients (Fig. 23.2) (Weller et al., 2014).
IDH mutations occur in approximately 5–10% of all
glioblastomas, are associated with younger age and bet-
ter outcome (Parsons et al., 2008), and rarely occur in
patients aged 65 years or older. Mutant IDH produces
the oncometabolite 2-hydroxyglutarate (Turcan et al.,
2012), which has been linked to a distinct epigenetic pat-
tern designated glioma CpG island methylator pheno-
type (G-CIMP) (Noushmehr et al., 2010). In contrast,
IDH wild-type glioblastoma is associated with older
age and poor prognosis; TERT promoter mutation marks
particularly poor outcome in these patients (Labussiere
386 H-G. WIRSCHING ET AL.
MRI
Contrast enhancing, diffusely infiltrating mass

Surgery/Biopsy
Gross total resection, if safely possible

Glioblastoma

Age < 65-70 years Age > 65-70 years

MGMT methylated MGMT unmethylated

TMZ/RT TMZ TMZ or TMZ/RT TMZ Hypofractionated RT

Repeat RT
Mostly stereotactic No firstline RT
1st RT >6 months Recurrent glioblastoma
Young age
Small tumors
Good KPS
Systemic therapies Surgery
contraindicated or Only if gross total resection is safely possible
failed

Combined?

TMZ Lomustine BEV

MGMT is prognostic
PD on TMZ dose-intensified
TMZ-free interval standard dose
Adequate
hematologic function required
MGMT is prognostic MGMT is prognostic
Suitable for most patients Benefit may be higher in
Adequate hematologic elderly patients with poor KPS
function required Recent hemorrhage/thromboembolism
are contraindications
Availability is restricted in the EU

Fig. 23.2. Therapeutic approach to glioblastoma. MRI, magnetic resonance imaging; MGMT, O6-methylguanyl DNA methyl-
transferase gene promoter; TMZ, temozolomide 150–200 mg/m2 on 5/28 days; TMZ/RT, 30  2 Gy ¼ 60 Gy with daily concom-
itant temozolomide at 75 mg/m2; hypofractionated RT, radiotherapy at 15  2.66 Gy ¼ 40 Gy; BEV, bevacizumab 10 mg/kg body
weight every 2 weeks; KPS, Karnofsky performance score; PD, progressive disease.

et al., 2014). Despite identical histopathologic appear-
ance, IDH wild-type and mutant glioblastomas consti-
tute two distinct molecular and prognostic entities that
are likely to be separated in future classifications of
brain tumors, as outlined in more detail in Chapter 5.
About half of all glioblastomas with EGFR amplifi-
cation (i.e., 20–25% of all IDH wild-type glioblastomas)
harbor a deletion within the extracellular ligand-binding
domain of EGFR (designated delta-EGFR or EGFRvIII)
that yields ligand-independent receptor activity (Aldape
et al., 2004). EGFRvIII is commonly expressed only in
a subset of EGFR-amplified cells (Nishikawa et al.,
2004), but preclinical and clinical data support a role
for EGFRvIII-positive cells as drivers of disease pro-
gression. The EGFRvIII protein interacts with wild-type
EGFR to drive cellular transformation and the glioma-
initiating cell phenotype via signal transducer and activa-
tor of transcription (STAT) 3 signaling (Fan et al., 2013),
and the EGFRvIII deletion mutation may confer poor
prognosis compared to EGFR-amplified glioblastoma
without co-occurrence of EGFRvIII (Shinojima et al.,
2003; Heimberger et al., 2005). Promising results with
vaccination targeting EGFRvIII in phase II clinical trials
have been reported (Sampson et al., 2010; Hegi et al.,
2012; Reardon et al., 2015).
Molecular signatures
Integrated large-scale analyses of genetic, epigenetic,
and expression data increasingly complement the
 GLIOBLASTOMA
understanding of the biology and yield continuous
refinement of the subclassification of glioblastoma
beyond histologic grading. In 2006 three gene expression
subtypes were defined by cluster analysis of 35 genes
that were correlated the strongest with survival in
76 patients with newly diagnosed anaplastic astrocytoma
or glioblastoma and termed proneural, mesenchymal,
and proliferative (Phillips et al., 2006). The proneural
subtype was associated with prolonged survival, youn-
ger age, and anaplastic histology and lacked alterations
of phosphatase and tensin homolog on chromosome
10 (PTEN) or EGFR. The proliferative and mesenchymal
subtypes expressed genes that were associated with pro-
liferation or angiogenesis, respectively, and survival was
poor. These analyses were extended to larger datasets
and complemented by mutation analyses in subsequent
years. In 2008, three altered key signaling pathways were
determined by The Cancer Genome Atlas project (2008),
namely receptor RTK/RAS/PI3K (88%), p53 (87%), and
retinoblastoma protein (78%), and in the same year,
IDH-1/2 mutations were discovered as a marker that
is strongly associated with secondary glioblastoma,
younger age, and better outcome (Parsons et al., 2008;
Yan et al., 2009). In 2010, the initially suggested gene
expression-based subclassification of glioblastoma was
further refined using 601 genes and sequence data
from 91 patients, yielding four subtypes designated pro-
neural, neural, classic, and mesenchymal, based on sim-
ilarities with known gene expression profiles (Verhaak
et al., 2010).
IDH-mutant glioblastomas constitute a subgroup of
proneural glioblastomas associated with G-CIMP
(Noushmehr et al., 2010). Of note, there is no association
of gene expression-based subtypes of G-CIMP with
MGMT promoter methylation (Bady et al., 2012). By
2012, epigenetic profiling yielded a classification of
six subtypes, four of which clustered within the pro-
neural gene expression subtype: two distinct histone
H3 (H3F3A) mutations, G34 and K27, were detected
in a large proportion of pediatric glioblastomas and these
mutations as well as IDH mutations were mutually
exclusive. These three subtypes share an association with
mutations of the tumor suppressor gene TP53. A fourth
proneural subgroup, designated RTK I, was character-
ized by upregulation of platelet-derived growth factor
receptor alpha (PDGFRA) and frequent deletions of
the CDKN2A gene encoding cyclin-dependent kinase
inhibitor 2A (Sturm et al., 2012). The nonproneural sub-
types were designated RTK II/classic, which is charac-
terized by frequent EGFR amplifications and
CDKN2A deletions, and the mesenchymal subtype.
These six subclasses were associated with distinct tumor
locations, age distributions, and prognosis. Only IDH-
mutant glioblastomas retain the good prognosis of
387
proneural glioblastoma, whereas G34, K27, and RTK
I are associated with poor prognosis that is comparable
to the two nonproneural subtypes (Sturm et al., 2012).
Meanwhile, the gene expression-based glioblastoma sub-
types have also been detected on the single cell level
within the same tumors, and an association of these gene
expression profiles with stemness-related genes and
glioma-initiating cells was suggested (Patel et al.,
2014). To date no therapeutic implications for clinical
routine are based on these global characterizations of
the molecular background of individual tumors. The
molecular subclassification of glioblastoma is discussed
in more detail in Chapter 6.
TREATMENT AND FOLLOW-UP
Surgery
Tissue is required to establish the diagnosis of glioblas-
toma, as outlined above. It can be obtained by stereotac-
tic or open biopsy, or by microsurgical resection of the
tumor. Biopsies are mostly performed as stereotactic
biopsies in patients with multifocal disease and in tumors
deemed unresectable due to their location in so-called
“eloquent” areas, i.e., areas that cannot be resected with-
out causing major disability. However, biopsies may not
yield enough tissue for molecular analyses and bear the
risk of sampling errors. The therapeutic value of micro-
surgical resection has been demonstrated best in a ran-
domized trial exploring the use of the fluorescent
label, 5-aminolevulinc acid, to facilitate gross total resec-
tion (Stummer et al., 2006). It is further supported by
numerous retrospective cohort studies, establishing
gross total resection as standard of care whenever
deemed feasible (Fig. 23.2). (Sanai et al., 2011; Weller
et al., 2014) Feasibility of this concept has also been dem-
onstrated for elderly patients aged 65 years or older:
Extent of resection was a prespecified, independent
prognostic factor in a survival model that controlled
for age, extent of resection, histology, MGMT status,
and study treatment among 371 elderly patients with ana-
plastic astrocytoma (n ¼ 40) or glioblastoma (n ¼ 331)
randomized to receive postoperative radiotherapy or
temozolomide chemotherapy within the NOA-08 trial
(Wick et al., 2012). Further, among 342 patients with
newly diagnosed glioblastoma aged 60 or older who
were randomized to two different radiotherapy regi-
mens or temozolomide, biopsy was associated with infe-
rior OS compared to surgical resection (HR, 1.50; 95%
CI, 1.17–1.92) in multivariate analyses controlling for
age, type of surgery, study treatment, and WHO perfor-
mance score (Malmstrom et al., 2012). The use of
5-aminolevulinic acid (see above) (Stummer et al.,
2006, 2008) or intraoperative imaging by ultrasound
or MRI may aid the surgeon to obtain the goal of an
388 H-G. WIRSCHING ET AL.
optimal resection (Rygh et al., 2008; Kubben et al., 2011),
while nuclear imaging with 18F-DOPA is currently in clin-
ical testing (NCT02020720).
Chemoradiotherapy
Daily concomitant temozolomide at 75 mg/m2 as an
adjunct to radiotherapy (30  2 Gy ¼ 60 Gy of the
involved field) followed by up to six cycles of temozolo-
mide at 150–200 mg/m2 on 5 of out 28 days prolonged
median OS compared to radiotherapy alone (14.6 versus
12.1 months; HR, 0.63; 95% CI, 0.52–0.75, p < 0.001)
(Stupp et al., 2005), but benefit from temozolomide
was mainly restricted to patients with MGMT promoter
methylation (Hegi et al., 2005). Patients aged older than
70 years were not included in this trial, and the subgroup
of patients aged 66–70 years appeared not to benefit
from combined chemoradiotherapy in post hoc analyses
(HR, 0.78; 95% CI, 0.50–1.25; p ¼ 0.29) (Laperriere et al.,
2013). The recently completed National Cancer Institute
of Canada CE6 phase III trial will define the efficacy of
combined chemoradiotherapy versus radiotherapy alone
in elderly patients with newly diagnosed glioblastoma
and good clinical performance (NCT00482677), but to
date combined chemoradiotherapy is the standard of
care only for fit elderly patients (Fig. 23.2) (Weller
et al., 2014).
Radiotherapy in elderly patients
Postoperative radiotherapy has activity in elderly
patients with glioblastoma, as demonstrated by a trial
that randomized 81 patients with glioblastoma and 2
patients with anaplastic astrocytoma aged 70 years or
older to either radiotherapy with best supportive care,
or best supportive care alone (median OS, 29.1 vs.
16.9 weeks; p ¼ 0.002) (Keime-Guibert et al., 2007).
These results were underpinned by a population-based
retrospective review of almost 3000 patients with glio-
blastoma aged 71–98 years (median age 76.9 years) after
adjusting for tumor size, location, type of surgery, and
demographics (HR, 0.43; 95% CI, 0.38–0.49) (Scott et al.,
2011). Radiotherapy in elderly patients with glioblastoma
is commonly administered as a hypofractionated proto-
col (Weller et al., 2014), based on a randomized trial in
95 patients aged 60 years or older that compared stan-
dard radiotherapy (30  2 Gy ¼ 60 Gy) versus hypofrac-
tionated radiotherapy (15  2.66 Gy ¼ 40 Gy), which
demonstrated comparable activity of both regimens
(HR, 0.90; 95% CI, 0.60–1.35; p ¼ 0.61) (Roa et al.,
2004). Among the intention-to-treat population of the
randomized Nordic trial, standard radiotherapy was
even inferior to hypofractionated radiotherapy with
10  3.4 Gy ¼ 34 Gy (OS 7.0 vs. 5.2 months; p ¼ 0.02).
Notably, one reason for the inferiority of standard
radiotherapy was likely that standard radiotherapy was
not completed by a substantial fraction of patients
(Malmstrom et al., 2012).
Chemotherapy in elderly patients
Postoperative chemotherapy with temozolomide is a
valid alternative to radiotherapy in elderly patients with
glioblastomas with MGMT promoter hypermethylation,
but not in patients with tumors without MGMT promoter
methylation (Fig. 23.2) (Weller et al., 2014). This was
demonstrated in parallel by two phase III clinical trials
in elderly patients: (1) the Nordic trial, which randomized
patients aged 60 years or older to receive temozolomide
dosed at 150–200 mg/m2 on 5 of out 28 days or one of
two radiotherapy regimens (discussed above) (Wick
et al., 2012); and (2) the NOA-08 trial, which randomized
patients aged 65 years or older with glioblastoma (89%)
or anaplastic astrocytoma (11%) to receive standard
radiotherapy or temozolomide at a dose-dense schedule
of 100 mg/m2 given on days 1–7 every other week
(1 week on/1 week off) (Wick et al., 2012). In the Nordic
trial, temozolomide (n ¼ 93) and hypofractionated radio-
therapy (n ¼ 98) were similarly effective (HR, 0.82; 96%
CI, 0.63–1.06), adjusted for age, type of surgery (biopsy
versus resection), and WHO performance score among
the intention-to-treat population (Malmstrom et al.,
2012). Efficacy analyses of the NOA-08 trial included
373 patients who received at least one dose of treatment
among a total of 412 randomized and 584 screened
patients. After adjustment for age, histologic diagnosis,
extent of resection, and MGMT promoter methylation,
temozolomide was noninferior to radiotherapy (HR,
1.09; 95% CI, 0.84–1.42) (Wick et al., 2012). Benefit from
temozolomide was predicted by MGMT promoter meth-
ylation in both trials and radiotherapy was favorable
among patients with tumors without MGMT promoter
methylation. Dose-intensified temozolomide regimens
became largely obsolete, because of greater toxicity,
but similar activity was noted compared to standard
temozolomide dosing at 150–200 mg/m2 on 5 out of
28 days in two phase III trials that directly compared
standard and dose-intensified temozolomide in patients
with newly diagnosed and recurrent glioblastoma (Brada
et al., 2010; Gilbert et al., 2013).
Antiangiogenic therapy
Angiogenesis is a defining characteristic of glioblastoma
that is driven by vascular endothelial growth factor
(VEGF) (Batchelor et al., 2014) and other mediators,
and the concept of targeting blood vessels to induce
“tumor starvation” has rendered VEGF an intensely
studied therapeutic target in a plethora of tumors beyond
glioblastoma (Folkman, 1971; Ellis and Hicklin, 2008;
 GLIOBLASTOMA 389
Grothey and Galanis, 2009). The anti-VEGF antibody age-stratified survival differences. Ongoing research is
bevacizumab is the antiangiogenic drug best studied in focusing on the identification of molecular markers
glioblastoma. It is commonly dosed at 10 mg/kg body predicting benefit from antiangiogenic therapies; to
weight intravenously every other week and is well toler- date, no such marker has been defined, but recently
ated by most patients. Arterial hypertension is the most association of the proneural subtype with benefit
common side-effect, and rare severe complications that from bevacizumab was reported in the AVAGlio trial
are associated with bevacizumab include hemorrhages, (Sandmann et al., 2015). In summary, the available evi-
thromboembolic events, complications of wound heal- dence currently does not support the administration of
ing, congestive heart failure, and gastrointestinal antiangiogenic therapy as a first-line postoperative
perforations. therapy in glioblastoma (Batchelor et al., 2014).
Two placebo-controlled phase III trials in patients
with newly diagnosed glioblastoma (RTOG 0825 and Response assessment
AVAGlio) noted prolonged progression-free survival
MRI is the method of choice to assess response to therapy
with the addition of bevacizumab to standard combined
in glioblastoma patients and is commonly performed
chemoradiotherapy (Chinot et al., 2014; Gilbert et al.,
every 2–3 months. Response is categorized as complete
2014). Less corticosteroid use, preserved general condi-
response, partial response, stable disease, and progressive
tion, and preserved quality of life were additional bene-
disease. Contrast enhancement on T1-weighted sequences
fits from bevacizumab reported in the AVAGlio trial
has been the standard measure to assess response in
(Chinot et al., 2014; Taphoorn et al., 2015), whereas the
glioblastoma for almost two decades (Macdonald et al.,
investigators of the RTOG 0825 trial noted stronger
1990), but was revisited due to increasing recognition
impairment of quality of life and neurocognitive decline
of “pseudoresponse” resulting from antiangiogenic
under bevacizumab (Gilbert et al., 2014). Reasons for
treatments, and of “pseudoprogression” resulting from
these conflicting data are speculative, but differences
radiotherapy or chemoradiotherapy (Wen et al., 2010).
in the response assessment within both trials may be
Pseudoresponse refers to a rapid decrease of contrast--
explanatory. The AVAGlio trial included measures to
enhancing lesions that may occur within hours of antian-
detect “pseudoresponse,” i.e., a sustained reduction in
giogenic treatment as a result of blood–brain barrier
contrast enhancement due to normalization of the
normalization. Pseudoprogression refers to a subacute,
blood–brain barrier (see below and Chapter 3), whereas
transient increase in the size of contrast-enhancing lesions
in the RTOG 0825 trial, early tumor progression may
after radiotherapy and appears to occur more frequently
have been missed due to the definition of progressive
under more intense combined chemoradiotherapy
disease solely based on contrast enhancement
(Brandsma et al., 2008). Pseudoprogression was identi-
(Batchelor et al., 2014). To date, three phase III trials
fied on the first MRI scans after radiotherapy in 9–31%
have failed to demonstrate an OS benefit from antian-
of patients with glioblastoma and contrast-enhancing
giogenic therapies in newly diagnosed glioblastoma,
anaplastic gliomas (de Wit et al., 2004; Brandsma et al.,
including the AVAGlio and RTOG 0825 trials of bevaci-
2008), but the precise frequency of pseudoprogression
zumab and a trial of the integrin inhibitor cilengitide
is difficult to estimate, because chemotherapy is usually
(Chinot et al., 2014; Gilbert et al., 2014; Stupp et al.,
continued when pseudoprogression is suspected, thus
2014a) The diverging results of improved progression-
precluding a differentiation of pseudoprogression from
free survival versus a lack of OS benefit in the AVAGlio
delayed treatment responses. The pathophysiology of
and RTOG 0825 trials may be attributed to substantial
pseudoprogression has not been clarified, but likely
crossover from the placebo-controlled arm to receive
constitutes a pronounced inflammatory response to
bevacizumab at progression (AVAGlio: 31.3%, RTOG
treatment yielding edema and disruption of the blood–
0825: 48.3%), or due to misdiagnosis of pseudoresponse,
brain barrier, which present as an increase in contrast
but this remains speculative (Batchelor et al., 2014). Fur-
enhancement on MRI scans. In most patients, pseudopro-
thermore, early reports suggested that particularly
gression is oligosymptomatic and transient, but severe
elderly patients in poor general condition might benefit
cases that correspond to treatment-induced necrosis
from bevacizumab (Nghiemphu et al., 2009; Lai et al.,
may require further treatment, as discussed in more detail
2011), but these patients were underrepresented in the
in Chapters 3 and 13.
AVAGlio and RTOG 0825 trials, because good general
condition was an inclusion criterion (Chinot et al.,
Recurrent glioblastoma
2014; Gilbert et al., 2014). A tendency to improved OS
in the bevacizumab group of the AVAGlio trial has Escape from antitumor therapy is caused by adaptations
indeed been noted with increasing age (Chinot et al., of the molecular machinery of tumor cells, mostly due
2014), but the trial was not powered to identify to selection of resistant, genetically distinct clones.
390 H-G. WIRSCHING ET AL.
Therefore, therapeutic options at progression depend on
previously administered therapies, but tumor character-
istics, availability, and local preferences are factors that
influence treatment choices, too. No standard of care for
the treatment of recurrent glioblastoma has been defined
and the efficacy of available treatment options at pro-
gression is commonly limited (Weller et al., 2013).
Repeat surgery may improve survival in some
patients, but this has not been validated in prospective
controlled trials. Data supporting second surgery at pro-
gression suggest that gross total resection, but not
incomplete resection, is beneficial (Fig. 23.2) (Bloch et al.,
2012; Suchorska et al., 2015). Other factors associated
with favorable outcome after repeat surgery apply to
approximately 1 in 4 patients with recurrent glioblastoma
and include age <70 years, Karnofsky performance
score >80% and small tumor volume (<50 cm3),
whereas involvement of functionally relevant
(“eloquent”) brain structures is associated with poor
postoperative survival (Park et al., 2010). The option
of repeat surgery should thus only be considered if the
risk for surgical complications is low, and if the general
condition of patients is estimated to remain good enough
postoperatively to allow for additional systemic therapy
(or repeat radiotherapy in selected cases, discussed
below). Surgery should not replace systemic therapy,
because infiltrating cells beyond the site of resection fre-
quently cannot be captured by neuroimaging, and these
cells can drive further tumor progression rapidly, even
when gross total resection is confirmed radiographically.
Hypofractionated radiotherapy is the treatment of
choice in elderly patients with tumors with MGMT pro-
moter methylation who received first-line postoperative
treatment with temozolomide alone, but the role of
repeat radiotherapy is less clear for all other patients
(Fig. 23.2). Some activity of repeat radiotherapy was
deduced from uncontrolled trials and retrospective data
analyses, but these included mostly patients with favor-
able prognostic factors due to smaller tumor volumes,
younger age, and better general condition (Dhermain
et al., 2004; Butowski et al., 2006). Repeat radiotherapy
should only be considered when the recurrence has
occurred after a relatively long interval from first radio-
therapy (at least >6 months) and when chemotherapy is
contraindicated or has failed. Even in these settings, the
unclear efficacy of repeat radiotherapy needs to be
weighed against the risk for complications that increases
with increasing cumulative radiation exposure of normal
brain, as discussed in more detail in Chapter 13. Recom-
mendations regarding dose or radiotherapy technique
vary based on the available evidence (Butowski et al.,
2006). Most commonly, 30–36 Gy are applied as frac-
tionated stereotactic radiotherapy with or without inten-
sity modulation (Combs et al., 2007), but no prospective
clinical trials have compared different radiotherapy
schedules in previously irradiated glioblastoma patients.
Systemic treatments are the mainstay of therapy for
recurrent glioblastoma (Fig. 23.2) and include single-
agent or combination treatments with nitrosoureas (in
particular, CCNU/lomustine), temozolomide, and beva-
cizumab (Weller et al., 2013). All of these options are well
tolerated by most patients. Lomustine dosed at
90–110 mg/m2 every 6 weeks is commonly utilized as a
control in clinical trials for recurrent glioblastoma and
progression-free survival rates at 6 months are in the
range of 19–25% (Wick et al., 2010; Batchelor et al.,
2013). In patients who appeared to derive benefit from
first-line temozolomide, rechallenge with temozolomide
is a viable option after a temozolomide-free interval
(Weller et al., 2015b; Brada et al., 2010). MGMT pro-
moter methylation is associated with prolonged survival
at temozolomide rechallenge (Weller et al., 2015b). Dose-
intensified temozolomide regimens have been studied
extensively, but standard dosing at 150–200 mg/m2 on
5/28 days may be preferred (Weller et al., 2014): more
toxicity, but no survival benefit from dose intensifica-
tion, was noted in two phase III trials directly comparing
standard and dose-intensified temozolomide in glioblas-
toma (Brada et al., 2010; Gilbert et al., 2013).
Accelerated approval by the US Food and Drug
Administration (FDA) and in various other countries
was obtained for bevacizumab for the treatment of
recurrent glioblastoma based on two uncontrolled phase
II trials based on durable response rate (Friedman et al.,
2009; Kreisl et al., 2009), but two trials of direct or indi-
rect small-molecule inhibitors of VEGF signaling,
cediranib and enzastaurin, in recurrent glioblastoma
failed to prolong survival (Wick et al., 2010; Batchelor
et al., 2013).
In the randomized noncomparative phase II BELOB
trial, a combination of lomustine with bevacizumab at
first recurrence of glioblastoma was well tolerated and
appeared to confer additive effects: median postrecur-
rence survival was 8 months with lomustine alone,
8 months with bevacizumab alone, and 12 months with
a combination of lomustine and bevacizumab (Taal
et al., 2014). A variety of other chemotherapy agents,
such as single-agent carboplatin, or procarbazine, have
also been used in the treatment of recurrent glioblastoma
patients, but given the lack of randomized data, their
benefit versus supportive care is unclear and at best
modest. The application of “tumor-treating fields” via
skin electrodes was equally active as physician’s best
choice in a phase III trial in patients with recurrent glio-
blastoma (Stupp et al., 2012) and was approved by the
FDA, the European Medicines Agency, and in various
other countries as a device based on these results
(Stupp et al., 2014b).
 GLIOBLASTOMA
In summary, therapeutic options at glioblastoma pro-
gression and effects on outcome are limited. Patients
recruited to controlled trials of recurrent glioblastoma
represent a subselection of patients with more favorable
prognosis, whereas best supportive care may be ade-
quate in a substantial fraction of patients who are heavily
impaired already at first recurrence. Symptomatic treat-
ment and psycho-oncologic interventions are therefore a
key aspect of the treatment of glioblastoma patients that
is increasingly moving into the focus in individual
patients with disease progression (Weller et al., 2014),
as discussed in more detail in Chapters 18 and 19.
EXPERIMENTAL APPROACHES
AND OUTLOOK
Progress in the molecular characterization of glioblas-
toma has led to the identification of a plethora of novel
treatment targets. Consequently, the traditional
histology-based WHO classification is increasingly com-
plemented by assessment of molecular markers, includ-
ing IDH and MGMT status. Taking the heterogeneity of
glioblastoma into account, a more personalized
approach to the treatment of glioblastoma is warranted.
A major challenge of molecular marker diagnostics that
may need to be resolved is intratumoral and temporal
heterogeneity of the molecular profile of glioblastoma
(Sottoriva et al., 2013; Ozawa et al., 2014; Patel
et al., 2014).
The concept of immunotherapy in treating glioblas-
toma has been explored for decades, with little or no suc-
cess (Wilson, 1979), but has moved back to the focus of
attention with the identification of promising targets,
technologic progress, and success of early clinical trials.
The term “tumor vaccination” refers to the activation of
the patient’s adaptive immune response against tumor-
specific antigens, in analogy to classic vaccination
against virus antigens (discussed in more detail in
Chapter 10).
One prominent example of a putative target for vac-
cination is the EGFRvIII deletion mutant, which harbors
a unique epitope that does not occur in normal cells
(Humphrey et al., 1990). Vaccination against this epitope
with the 13-amino-acid peptide rindopepimut was dem-
onstrated to be effective in triggering an immunologic
response against EGFRvIII-positive cells in single-arm
phase II trials, in patients with newly diagnosed glioblas-
toma who received rindopepimut in addition to standard
chemoradiotherapy (Sampson et al., 2010; Schuster
et al., 2015). Results from the double-blinded ACT IV
phase III trial evaluating the efficacy of rindopepimut
are currently awaited (NCT01480479).
Besides utilizing peptides, adaptive immune responses
can be evoked by isolating a patient’s antigen-presenting
391
cells (mostly dendritic cells) from peripheral blood, puls-
ing these cells in vitro, and returning them to the patient.
Dendritic cells will then activate T-cell clones and thereby
boost specific immune responses (Thomas et al., 2012).
The efficacy of a platform technology utilizing auto-
logous dendritic cells pulsed with the patient’s tumor
lysate (DCVax) is currently being evaluated in a double-
blind phase III trial in patients with unresectable or
recurrent glioblastoma (NCT00045968). In a phase II trial
in patients with newly diagnosed glioblastoma, auto-
logous dendritic cells pulsed with epitopes from six
glioblastoma- and glioma-initiating cell-associated pro-
teins (ICT-107) as an adjunct to standard chemoradiother-
apy prolonged progression-free survival by 2.4 months
(HR, 0.54; p ¼ 0.006) compared to controls who received
unpulsed dendritic cells (Wen et al., 2014a). The efficacy
of this concept will be explored in a phase III trial in the
near future. However, immune escape is one of the
hallmarks of glioblastoma, and cytotoxic therapies and
steroids are likely counterproductive in supporting
immune-mediated antitumor responses (Weller et al.,
2015a). Utilizing humanized monoclonal antibodies tar-
geting the programmed death protein (PD)1 (nivolumab,
pembrolizumab) or the cytotoxic T-lymphocyte antigen
(CTLA) 4 (ipilimumab) to counteract tumor cell-mediated
suppression of the adaptive immune response has proven
successful in malignant melanoma (Hodi et al., 2010;
Ribas et al., 2013; Wolchok et al., 2013) and nonsmall
cell lung cancer (Brahmer et al., 2015; Rizvi et al.,
2015). These agents are currently evaluated in various
early trials and one phase III trial in recurrent glioblas-
toma (NCT02017717); the rationale for these treatments
is supported by the association of low expression of the
PD1 ligand on blood monocytes with improved survival
among patients with newly diagnosed glioblastoma
treated with an autologous heat shock protein peptide
vaccine as an adjunct to standard chemoradiotherapy
(Bloch et al., 2015).
Other emerging targets for vaccination include the
tumor-specific epitope of mutant IDH, which evoked
an adaptive immune response in preclinical studies
(Schumacher et al., 2014), and the herpesvirus cytomeg-
alovirus antigen pp65, which triggered dendritic cell-
mediated immune response against glioblastoma cells
in a preliminary study of 12 patients (Mitchell et al.,
2015). Of note, the immune response in this setting
was further triggered by tetanus/diphtheria toxoid,
which may thus be further evaluated as a booster of
immune responses against glioblastoma cells (Mitchell
et al., 2015).
Other approaches include viruses used both as vectors
for somatic gene therapy by targeting molecular path-
ways that mediate malignancy and as oncolytic viruses
that provoke an inflammatory host response or kill
392 H-G. WIRSCHING ET AL.
glioma cells directly by excessive replication, with uncer-
tain success in clinical trials (Kaufmann and Chiocca,
2014). These concepts are discussed in more detail in
Chapter 11.
Other means to target the molecular machinery that
drives malignancy in glioblastoma are small molecules
that interfere with enzyme functions. IDH point muta-
tions are biologically relevant, early glioma-initiating
events that are present in approximately 10% of glioblas-
tomas (Parsons et al., 2008) and thus considered a prime
therapeutic target. A small-molecule inhibitor of mutant
IDH function has shown promising preclinical results
that require clinical exploration (Rohle et al., 2013).
Amplification of EGFR is another central glioma-
associated molecular signature that is mutually exclusive
with IDH mutations and occurs in approximately half of
all IDH wild-type glioblastomas (Cancer Genome Atlas
Research, 2008; Ozawa et al., 2014). To date, various
small-molecule inhibitors targeting EGFR in glioblas-
toma yielded disappointing results as single-agent ther-
apies, but notably, none of these trials selected for
patients with EGFR amplification (Hegi et al., 2012)
and their blood–brain barrier penetration was uniformly
suboptimal. Furthermore, various other RTK share parts
of the downstream signaling pathway with EGFR and
therefore, other RTK may compensate for blocking of
EGFR. Yet, combination therapies have not been
explored in cohorts that were preselected based on
molecular characteristics (Hegi et al., 2012). Two
early-phase trials in unselected patients with recurrent
glioblastoma explored combination treatments of the
EGFR inhibitor erlotinib or of the multi-RTK inhibitor
sorafenib in combination with temsirolimus (CCI-779),
an inhibitor of the downstream RTK convergence mol-
ecule mammalian target of rapamycine (mTOR), with
disappointing results (Lee et al., 2012; Wen et al.,
2014b). Inhibition of mTOR-utilizing temsirolimus was
also explored as an adjunct to standard chemoradiother-
apy in patients with newly diagnosed glioblastoma and
an unmethylated MGMT promoter, but preliminary
results are disappointing, too (Wick et al., 2014).
An important conclusion from these and other clini-
cal trials utilizing inhibitors of RTK signaling was that
proving the presence of molecular targets in individual
tumors is necessary in order to accurately assess efficacy
of these targeted agents. Examples of ongoing clinical
trials that apply such molecular entry controls include
a phase II trial in newly diagnosed glioblastoma with
activating fibroblast growth factor fusion proteins and
activating mutations (NCT01975701), which are present
in less than 5% of all glioblastomas, or trials in recurrent
glioblastoma utilizing an inhibitor of PI3K alone or
in combinations with different antiangiogenic agents
(NCT01339052, NCT01870726, NCT01349660).
As outlined above, glioma-initiating cells are thought
to constitute a subpopulation that mediate recurrence
and resistance to standard chemoradiotherapy, but to
date, attempts to target signaling cascades deemed spe-
cific for glioma-initiating cells have been disappointing
in early clinical trials (Thomas et al., 2014). Other emerg-
ing treatments include low-intensity, intermediate-
frequency electric fields applied to the head of patients
with the use of an electrode device. Although the exact
mechanism of action is under active investigation and
thought to be mediated via mitotic arrest, results of an
interim analysis of a phase III trial evaluating this
option as an adjunct to standard chemoradiotherapy in
newly diagnosed glioblastoma were promising (Stupp
et al., 2014b).
In summary, the exponentially growing understand-
ing of the molecular mechanisms that drive glioblastoma
has not yet translated into survival benefit. Thorough
patient selection for clinical trials and probably combina-
tion treatments, oriented at the molecular profile of indi-
vidual tumors, may ultimately improve outcome.
REFERENCES
Aldape KD, Ballman K, Furth A et al. (2004).
Immunohistochemical detection of EGFRvIII in high
malignancy grade astrocytomas and evaluation of prognos-
tic significance. J Neuropathol Exp Neurol 63: 700–707.
Arita N, Taneda M, Hayakawa T (1994). Leptomeningeal
dissemination of malignant gliomas. Incidence, diagnosis
and outcome. Acta Neurochir (Wien) 126: 84–92.
Awad I, Bay JW, Rogers L (1986). Leptomeningeal metastasis
from supratentorial malignant gliomas. Neurosurgery 19:
247–251.
Bady P, Scuiscio D, Diserens AC et al. (2012). MGMT meth-
ylation analysis of glioblastoma on the Infinium methyla-
tion BeadChip identifies two distinct CpG regions
associated with gene silencing and outcome, yielding a pre-
diction model for comparisons across datasets, tumor
grades, and CIMP-status. Acta Neuropathol 124: 547–560.
Bao S, Wu Q, McLendon RE et al. (2006). Glioma stem cells
promote radioresistance by preferential activation of the
DNA damage response. Nature 444: 756–760.
Batchelor TT, Reardon DA, de Groot JF et al. (2013). Phase III
randomized trial comparing the efficacy of cediranib as
monotherapy, and in combination with lomustine, versus
lomustine alone in patients with recurrent glioblastoma.
J Clin Oncol 31: 3212–3218.
Batchelor TT, Reardon DA, de Groot JF et al. (2014).
Antiangiogenic therapy for glioblastoma: current status
and future prospects. Clin Cancer Res 20: 5612–5619.
Beier D, Rohrl S, Pillai DR et al. (2008). Temozolomide pref-
erentially depletes cancer stem cells in glioblastoma.
Cancer Res 68: 5706–5715.
Bloch O, Han SJ, Cha S et al. (2012). Impact of extent of resec-
tion for recurrent glioblastoma on overall survival: clinical
article. J Neurosurg 117: 1032–1038.
 GLIOBLASTOMA
Bloch O, Raizer JJ, Lim M et al. (2015). Newly diagnosed glio-
blastoma patients treated with an autologous heat shock
protein peptide vaccine: PD-L1 expression and response
to therapy. J Clin Oncol (suppl): abstr 2011.
Bondy ML, Scheurer ME, Malmer B et al. (2008). Brain tumor
epidemiology: consensus from the Brain Tumor
Epidemiology Consortium. Cancer 113: 1953–1968.
Brada M, Ford D, Ashley S et al. (1992). Risk of second brain
tumour after conservative surgery and radiotherapy for
pituitary adenoma. Br Med J 304: 1343–1346.
Brada M, Stenning S, Gabe R et al. (2010). Temozolomide ver-
sus procarbazine, lomustine, and vincristine in recurrent
high-grade glioma. J Clin Oncol 28: 4601–4608.
Brahmer J, Reckamp KL, Baas P et al. (2015). Nivolumab
versus docetaxel in advanced squamous-cell non-small-
cell lung cancer. N Engl J Med 373: 123–135.
Brandsma D, Stalpers L, Taal W et al. (2008). Clinical fea-
tures, mechanisms, and management of pseudoprogression
in malignant gliomas. Lancet Oncol 9: 453–461.
Butowski NA, Sneed PK, Chang SM (2006). Diagnosis and
treatment of recurrent high-grade astrocytoma. J Clin
Oncol 24: 1273–1280.
Cancer Genome Atlas Research (2008). Comprehensive geno-
mic characterization defines human glioblastoma genes
and core pathways. Nature 455: 1061–1068.
Capper D, Zentgraf H, Balss J et al. (2009). Monoclonal anti-
body specific for IDH1 R132H mutation. Acta Neuropathol
118: 599–601.
Chaichana KL, Parker SL, Olivi A et al. (2009). Long-term
seizure outcomes in adult patients undergoing primary
resection of malignant brain astrocytomas. Clinical article.
J Neurosurg 111: 282–292.
Chen J, Li Y, Yu TS et al. (2012). A restricted cell population
propagates glioblastoma growth after chemotherapy.
Nature 488: 522–526.
Cheng L, Huang Z, Zhou W et al. (2013). Glioblastoma stem
cells generate vascular pericytes to support vessel function
and tumor growth. Cell 153: 139–152.
Chinot OL, Wick W, Mason M et al. (2014). Bevacizumab plus
radiotherapy-temozolomide for newly diagnosed glioblas-
toma. N Engl J Med 370: 709–722.
Collignon FP, Holland EC, Feng S (2004). Organ donors with
malignant gliomas: an update. Am J Transplant 4: 15–21.
Combs SE, Debus J, Schulz-Ertner D (2007). Radiotherapeutic
alternatives for previously irradiated recurrent gliomas.
BMC Cancer 7: 167.
Connelly JM, Malkin MG (2007). Environmental risk factors
for brain tumors. Curr Neurol Neurosci Rep 7: 208–214.
de Wit MC, de Bruin HG, Eijkenboom W et al. (2004).
Immediate post-radiotherapy changes in malignant glioma
can mimic tumor progression. Neurology 63: 535–537.
Dhermain F, de Crevoisier R, Parker F et al. (2004). Role of
radiotherapy in recurrent gliomas. Bull Cancer 91: 883–889.
Djalilian HR, Shah MV, Hall WA (1999). Radiographic inci-
dence of multicentric malignant gliomas. Surg Neurol 51:
554–557. discussion 557–558.
Dziurzynski K, Chang SM, Heimberger AB et al. (2012).
Consensus on the role of human cytomegalovirus in
glioblastoma. Neuro Oncol 14: 246–255.
393
El Ali A, Hermann DM (2011). ATP-binding cassette trans-
porters and their roles in protecting the brain.
Neuroscientist 17: 423–436.
Ellingson BM, Zaw T, Cloughesy TF et al. (2012).
Comparison between intensity normalization techniques
for dynamic susceptibility contrast (DSC)-MRI estimates
of cerebral blood volume (CBV) in human gliomas.
J Magn Reson Imaging 35: 1472–1477.
Ellingson BM, Lai A, Harris RJ et al. (2013). Probabilistic
radiographic atlas of glioblastoma phenotypes. AJNR
Am J Neuroradiol 34: 533–540.
Ellis LM, Hicklin DJ (2008). VEGF-targeted therapy: mecha-
nisms of anti-tumour activity. Nat Rev Cancer 8: 579–591.
Eriksson PS, Perfilieva E, Bjork-Eriksson T et al. (1998).
Neurogenesis in the adult human hippocampus. Nat Med
4: 1313–1317.
Erlich SS, Davis RL (1978). Spinal subarachnoid metastasis
from primary intracranial glioblastoma multiforme.
Cancer 42: 2854–2864.
Fan QW, Cheng CK, Gustafson WC et al. (2013). EGFR phos-
phorylates tumor-derived EGFRvIII driving STAT3/5 and
progression in glioblastoma. Cancer Cell 24: 438–449.
Fecci PE, Heimberger AB, Sampson JH (2014). Immunotherapy
for primary brain tumors: no longer a matter of privilege. Clin
Cancer Res 20: 5620–5629.
Folkman J (1971). Tumor angiogenesis: therapeutic implica-
tions. N Engl J Med 285: 1182–1186.
Friedman HS, Prados MD, Wen PY et al. (2009). Bevacizumab
alone and in combination with irinotecan in recurrent glio-
blastoma. J Clin Oncol 27: 4733–4740.
Gallego Perez-Larraya J, Ducray F, Chinot O et al. (2011).
Temozolomide in elderly patients with newly diagnosed
glioblastoma and poor performance status: an ANOCEF
phase II trial. J Clin Oncol 29: 3050–3055.
Gilbert MR, Wang M, Aldape KD et al. (2013). Dose-dense
temozolomide for newly diagnosed glioblastoma: a ran-
domized phase III clinical trial. J Clin Oncol 31: 4085–4091.
Gilbert MR, Dignam JJ, Armstrong TS et al. (2014).
A randomized trial of bevacizumab for newly diagnosed
glioblastoma. N Engl J Med 370: 699–708.
Gilbertson RJ, Rich JN (2007). Making a tumour’s bed: glio-
blastoma stem cells and the vascular niche. Nat Rev Cancer
7: 733–736.
Grabb PA, Albright AL, Pang D (1992). Dissemination of
supratentorial malignant gliomas via the cerebrospinal
fluid in children. Neurosurgery 30: 64–71.
Grothey A, Galanis E (2009). Targeting angiogenesis: pro-
gress with anti-VEGF treatment with large molecules.
Nat Rev Clin Oncol 6: 507–518.
Han SJ, Yang I, Tihan T et al. (2010). Primary gliosarcoma: key
clinical and pathologic distinctions from glioblastoma with
implications as a unique oncologic entity. J Neurooncol 96:
313–320.
Hegi ME, Diserens AC, Gorlia T et al. (2005). MGMT gene
silencing and benefit from temozolomide in glioblastoma.
N Engl J Med 352: 997–1003.
Hegi ME, Rajakannu P, Weller M (2012). Epidermal growth
factor receptor: a re-emerging target in glioblastoma.
Curr Opin Neurol 25: 774–779.
394 H-G. WIRSCHING ET AL.
Heimberger AB, Hlatky R, Suki D et al. (2005). Prognostic
effect of epidermal growth factor receptor and EGFRvIII
in glioblastoma multiforme patients. Clin Cancer Res 11:
1462–1466.
Herrlinger U, Forschler H, Kuker W et al. (2004).
Leptomeningeal metastasis: survival and prognostic fac-
tors in 155 patients. J Neurol Sci 223: 167–178.
Hodi FS, O’Day SJ, McDermott MF et al. (2010). Improved
survival with ipilimumab in patients with metastatic mela-
noma. N Engl J Med 363: 711–723.
Humphrey PA, Wong AJ, Vogelstein B et al. (1990). Anti-
synthetic peptide antibody reacting at the fusion junction of
deletion-mutant epidermal growth factor receptors in human
glioblastoma. Proc Natl Acad Sci U S A 87: 4207–4211.
Interphone Study Group (2010). Brain tumour risk in relation to
mobile telephone use: results of the INTERPHONE inter-
national case-control study. Int J Epidemiol 39: 675–694.
Karsy M, Gelbman M, Shah P et al. (2012). Established and
emerging variants of glioblastoma multiforme: review of
morphological and molecular features. Folia Neuropathol
50: 301–321.
Kaufmann JK, Chiocca EA (2014). Glioma virus therapies
between bench and bedside. Neuro Oncol 16: 334–351.
Keime-Guibert F, Chinot O, Taillandier L et al. (2007).
Radiotherapy for glioblastoma in the elderly. N Engl
J Med 356: 1527–1535.
Kerkhof M, Dielemans JC, van Breemen MS et al. (2013).
Effect of valproic acid on seizure control and on survival
in patients with glioblastoma multiforme. Neuro Oncol
15: 961–967.
Kickingereder P, Wiestler B, Sahm F et al. (2014). Primary
central nervous system lymphoma and atypical glioblas-
toma: multiparametric differentiation by using diffusion-,
perfusion-, and susceptibility-weighted MR imaging.
Radiology 272: 843–850.
Kono K, Inoue Y, Nakayama K et al. (2001). The role of
diffusion-weighted imaging in patients with brain tumors.
AJNR Am J Neuroradiol 22: 1081–1088.
Korshunov A, Sycheva R, Golanov A et al. (2007). Gains at the
1p36 chromosomal region are associated with symptomatic
leptomeningeal dissemination of supratentorial glioblasto-
mas. Am J Clin Pathol 127: 585–590.
Kozak KR, Moody JS (2009). Giant cell glioblastoma: a glio-
blastoma subtype with distinct epidemiology and superior
prognosis. Neuro Oncol 11: 833–841.
Kozak KR, Mahadevan A, Moody JS (2009). Adult gliosar-
coma: epidemiology, natural history, and factors associated
with outcome. Neuro Oncol 11: 183–191.
Kreisl TN, Kim L, Moore K et al. (2009). Phase II trial of
single-agent bevacizumab followed by bevacizumab plus
irinotecan at tumor progression in recurrent glioblastoma.
J Clin Oncol 27: 740–745.
Kubben PL, ter Meulen KJ, Schijns OE et al. (2011).
Intraoperative MRI-guided resection of glioblastoma mul-
tiforme: a systematic review. Lancet Oncol 12: 1062–1070.
La Fougere C, Suchorska B, Bartenstein P et al. (2011).
Molecular imaging of gliomas with PET: opportunities
and limitations. Neuro Oncol 13: 806–819.
Labussiere M, Di Stefano AL, Gleize V et al. (2014). TERT pro-
moter mutations in gliomas, genetic associations and clinico-
pathological correlations. Br J Cancer 111: 2024–2032.
Lacroix M, Abi-Said D, Fourney DR et al. (2001).
A multivariate analysis of 416 patients with glioblastoma
multiforme: prognosis, extent of resection, and survival.
J Neurosurg 95: 190–198.
Lai A, Tran A, Nghiemephu PL et al. (2011). Phase II study of
bevacizumab plus temozolomide during and after radiation
therapy for patients with newly diagnosed glioblastoma
multiforme. J Clin Oncol 29: 142–148.
Laperriere N, Weller M, Stupp R et al. (2013). Optimal man-
agement of elderly patients with glioblastoma. Cancer
Treat Rev 39: 350–357.
Lathia JD, Gallagher J, Heddleston JM et al. (2010). Integrin
alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:
421–432.
Law M, Yang S, Wang H et al. (2003). Glioma grading: sen-
sitivity, specificity, and predictive values of perfusion MR
imaging and proton MR spectroscopic imaging compared
with conventional MR imaging. AJNR Am J Neuroradiol
24: 1989–1998.
Lee EQ, Kuhn J, Lamborn KR et al. (2012). Phase I/II study of
sorafenib in combination with temsirolimus for recurrent
glioblastoma or gliosarcoma: North American Brain
Tumor Consortium study 05-02. Neuro Oncol 14: 1511–1518.
Lindsay A, Holthouse D, Robbins P et al. (2002). Spinal lep-
tomeningeal metastases following glioblastoma multi-
forme treated with radiotherapy. J Clin Neurosci 9:
725–728.
Louis DN, Ohgaki H, Wiestler OD et al. (2007). The 2007
WHO classification of tumours of the central nervous sys-
tem. Acta Neuropathol 114: 97–109.
Macdonald DR, Cascino TL, Schold Jr SC et al. (1990).
Response criteria for phase II studies of supratentorial
malignant glioma. J Clin Oncol 8: 1277–1280.
Malmstrom A, Gronberg BH, Marosi C et al. (2012).
Temozolomide versus standard 6-week radiotherapy ver-
sus hypofractionated radiotherapy in patients older than
60 years with glioblastoma: the Nordic randomised, phase
3 trial. Lancet Oncol 13: 916–926.
Mashimo T, Pichumani K, Vemireddy V et al. (2014). Acetate
is a bioenergetic substrate for human glioblastoma and
brain metastases. Cell 159: 1603–1614.
Minniti G, Traish D, Ashley S et al. (2005). Risk of second
brain tumor after conservative surgery and radiotherapy
for pituitary adenoma: update after an additional 10 years.
J Clin Endocrinol Metab 90: 800–804.
Mitchell DA, Batich KA, Gunn MD et al. (2015). Tetanus tox-
oid and CCL3 improve dendritic cell vaccines in mice and
glioblastoma patients. Nature 519: 366–369.
Neglia JP, Robison LL, Stovall M et al. (2006). New primary
neoplasms of the central nervous system in survivors of
childhood cancer: a report from the Childhood Cancer
Survivor Study. J Natl Cancer Inst 98: 1528–1537.
Nghiemphu PL, Liu W, Lee Y et al. (2009). Bevacizumab and
chemotherapy for recurrent glioblastoma: a single-
institution experience. Neurology 72: 1217–1222.
 GLIOBLASTOMA
Nishikawa R, Sugiyama T, Narita Y et al. (2004).
Immunohistochemical analysis of the mutant epidermal
growth factor, deltaEGFR, in glioblastoma. Brain
Tumor Pathol 21: 53–56.
Noushmehr H, Weisenberger DJ, Diefes K et al. (2010).
Identification of a CpG island methylator phenotype that
defines a distinct subgroup of glioma. Cancer Cell 17:
510–522.
Nunes MC, Roy NS, Keyoung HM et al. (2003). Identification
and isolation of multipotential neural progenitor cells from
the subcortical white matter of the adult human brain. Nat
Med 9: 439–447.
Ohgaki H, Kim YH, Steinbach JP (2010). Nervous system
tumors associated with familial tumor syndromes. Curr
Opin Neurol 23: 583–591.
Ostrom QT, Barnholtz-Sloan JS (2011). Current state of our
knowledge on brain tumor epidemiology. Curr Neurol
Neurosci Rep 11: 329–335.
Ostrom QT, Gittleman H, Liao P et al. (2014a). CBTRUS sta-
tistical report: primary brain and central nervous system
tumors diagnosed in the United States in 2007–2011.
Neuro Oncol 16 (Suppl 4): iv1–iv63.
Ostrom QT, Bauchet L, Davis FG et al. (2014b). The epidemi-
ology of glioma in adults: a “state of the science” review.
Neuro Oncol 16: 896–913.
Ostrom QT, de Blank PM, Kruchko C et al. (2015). Alex’s
Lemonade Stand Foundation infant and childhood primary
brain and central nervous system tumors diagnosed in the
United States in 2007–2011. Neuro Oncol 16 (Suppl 10):
x1–x36.
Ozawa T, Riester M, Cheng YK et al. (2014). Most human
non-GCIMP glioblastoma subtypes evolve from a common
proneural-like precursor glioma. Cancer Cell 26: 288–300.
Park JK, Hodges T, Arko L et al. (2010). Scale to predict sur-
vival after surgery for recurrent glioblastoma multiforme.
J Clin Oncol 28: 3838–3843.
Parsons DW, Jones S, Zhang X et al. (2008). An integrated
genomic analysis of human glioblastoma multiforme.
Science 321: 1807–1812.
Patel AP, Tirosh I, Trombetta JJ et al. (2014). Single-cell
RNA-seq highlights intratumoral heterogeneity in primary
glioblastoma. Science 344: 1396–1401.
Phillips HS, Kharbanda S, Chen R et al. (2006). Molecular sub-
classes of high-grade glioma predict prognosis, delineate a
pattern of disease progression, and resemble stages in neu-
rogenesis. Cancer Cell 9: 157–173.
Pietras A, Katz AM, Ekstrom EJ et al. (2014). Osteopontin-
CD44 signaling in the glioma perivascular niche enhances
cancer stem cell phenotypes and promotes aggressive
tumor growth. Cell Stem Cell 14: 357–369.
Reardon DA, Schuster JM, Tran DD et al. (2015). 107 ReACT:
overall survival from a randomized phase II study of rindo-
pepimut (CDX-110) plus bevacizumab in relapsed glio-
blastoma. Neurosurgery 62 (Suppl 1): 198–199.
Ribas A, Kefford R, Marshall M et al. (2013). Phase III ran-
domized clinical trial comparing tremelimumab with
standard-of-care chemotherapy in patients with advanced
melanoma. J Clin Oncol 31: 616–622.
395
Ricci-Vitiani L, Pallini R, Biffoni M et al. (2010). Tumour vas-
cularization via endothelial differentiation of glioblastoma
stem-like cells. Nature 468: 824–828.
Rizvi NA, Mazieres J, Planchard D et al. (2015). Activity and
safety of nivolumab, an anti-PD-1 immune checkpoint
inhibitor, for patients with advanced, refractory squamous
non-small-cell lung cancer (CheckMate 063): a phase 2,
single-arm trial. Lancet Oncol 16: 257–265.
Roa W, Brasher PM, Bauman G et al. (2004). Abbreviated
course of radiation therapy in older patients with glioblas-
toma multiforme: a prospective randomized clinical trial.
J Clin Oncol 22: 1583–1588.
Rohle D, Popovici-Muller J, Palaskas N et al. (2013). An inhib-
itor of mutant IDH1 delays growth and promotes differen-
tiation of glioma cells. Science 340: 626–630.
Ron E, Modan B, Boice Jr JD et al. (1988). Tumors of the brain
and nervous system after radiotherapy in childhood. N Engl
J Med 319: 1033–1039.
Rygh OM, Selbekk T, Torp SH et al. (2008). Comparison of
navigated 3D ultrasound findings with histopathology in
subsequent phases of glioblastoma resection. Acta
Neurochir (Wien) 150: 1033–1041. discussion 1042.
Sadetzki S, Chetrit A, Freedman L et al. (2005). Long-term
follow-up for brain tumor development after childhood
exposure to ionizing radiation for tinea capitis. Radiat
Res 163: 424–432.
Sampson JH, Heimberger AB, Archer GE et al. (2010).
Immunologic escape after prolonged progression-free sur-
vival with epidermal growth factor receptor variant III pep-
tide vaccination in patients with newly diagnosed
glioblastoma. J Clin Oncol 28: 4722–4729.
Sanai N, Tramontin AD, Quinones-Hinojosa A et al. (2004).
Unique astrocyte ribbon in adult human brain contains neu-
ral stem cells but lacks chain migration. Nature 427:
740–744.
Sanai N, Alvarez-Buylla A, Berger MS (2005). Neural stem
cells and the origin of gliomas. N Engl J Med 353: 811–822.
Sanai N, Polley MY, McDermott MW et al. (2011). An extent
of resection threshold for newly diagnosed glioblastomas.
J Neurosurg 115: 3–8.
Sandmann T, Bourgon R, Garcia J et al. (2015). Patients with
proneural glioblastoma may derive overall survival benefit
from the addition of bevacizumab to first-line radiotherapy
and temozolomide: retrospective analysis of the AVAglio
trial. J Clin Oncol 33: 2735–2744.
Schumacher T, Bunse L, Pusch S et al. (2014). A vaccine tar-
geting mutant IDH1 induces antitumour immunity. Nature
512: 324–327.
Schuster J, Lai RK, Recht LD et al. (2015). A phase II, multi-
center trial of rindopepimut (CDX-110) in newly diag-
nosed glioblastoma: the ACT III study. Neuro Oncol 17:
854–861.
Schweitzer T, Vince GH, Herbold C et al. (2001). Extraneural
metastases of primary brain tumors. J Neurooncol 53:
107–114.
Scott J, Tsai YY, Chinnaiyan P et al. (2011). Effectiveness of
radiotherapy for elderly patients with glioblastoma. Int
J Radiat Oncol Biol Phys 81: 206–210.
396 H-G. WIRSCHING ET AL.
Shinojima N, Tada K, Shiraishi S et al. (2003). Prognostic
value of epidermal growth factor receptor in patients with
glioblastoma multiforme. Cancer Res 63: 6962–6970.
Simpson JR, Horton J, Scott C et al. (1993). Influence of loca-
tion and extent of surgical resection on survival of patients
with glioblastoma multiforme: results of three consecutive
Radiation Therapy Oncology Group (RTOG) clinical trials.
Int J Radiat Oncol Biol Phys 26: 239–244.
Singh SK, Hawkins C, Clarke ID et al. (2004). Identification of
human brain tumour initiating cells. Nature 432: 396–401.
Son MJ, Woolard K, Nam DH et al. (2009). SSEA-1 is an
enrichment marker for tumor-initiating cells in human glio-
blastoma. Cell Stem Cell 4: 440–452.
Sottoriva A, Spiteri I, Piccirillo SG et al. (2013). Intratumor
heterogeneity in human glioblastoma reflects cancer
evolutionary dynamics. Proc Natl Acad Sci U S A 110:
4009–4014.
Stummer W, Pichlmeier U, Meinel T et al. (2006).
Fluorescence-guided surgery with 5-aminolevulinic acid
for resection of malignant glioma: a randomised controlled
multicentre phase III trial. Lancet Oncol 7: 392–401.
Stummer W, Reulen HJ, Meinel T et al. (2008). Extent of
resection and survival in glioblastoma multiforme: identi-
fication of and adjustment for bias. Neurosurgery 62:
564–576. discussion 564–576.
Stupp R, Mason WP, van den Bent MJ et al. (2005).
Radiotherapy plus concomitant and adjuvant temozolo-
mide for glioblastoma. N Engl J Med 352: 987–996.
Stupp R, Wong ET, Kanner AA et al. (2012). NovoTTF-100A
versus physician’s choice chemotherapy in recurrent glio-
blastoma: a randomised phase III trial of a novel treatment
modality. Eur J Cancer 48: 2192–2202.
Stupp R, Hegi MF, Gorlia T et al. (2014a). Cilengitide com-
bined with standard treatment for patients with newly diag-
nosed glioblastoma with methylated MGMT promoter
(CENTRIC EORTC 26071-22072 study): a multicentre,
randomised, open-label, phase 3 trial. Lancet Oncol 15:
1100–1108.
Stupp R, Wong E, Scott C et al. (2014b). Interim analysis of the
EF-14 trial: a prospective, multi-center trial of NovoTTF-
100A together with temozolomide compared to temozolo-
mide alone in patients with newly diagnosed GBM. Neuro
Oncol 16: v167.
Sturm D, Witt H, Hovestadt V et al. (2012). Hotspot mutations
in H3F3A and IDH1 define distinct epigenetic and biolog-
ical subgroups of glioblastoma. Cancer Cell 22: 425–437.
Suchorska B, Weller M, Tabatabai G et al. (2015). Complete
resection of contrast-enhancing tumor volume is associated
with improved survival in recurrent glioblastoma results
from the DIRECTOR trial. Neurosurgery 62 (Suppl 1): 209.
Taal W, Oosterkamp HM, Walenkamp AM et al. (2014).
Single-agent bevacizumab or lomustine versus a combina-
tion of bevacizumab plus lomustine in patients with recur-
rent glioblastoma (BELOB trial): a randomised controlled
phase 2 trial. Lancet Oncol 15: 943–953.
Taphoorn MJ, Stupp R, Coens C et al. (2005). Health-related
quality of life in patients with glioblastoma: a randomised
controlled trial. Lancet Oncol 6: 937–944.
Taphoorn MJ, Henriksson R, Bottomley M et al. (2015). Health-
related quality of life in a randomized phase III study of
bevacizumab, temozolomide, and radiotherapy in newly
diagnosed glioblastoma. J Clin Oncol 33: 2166–2175.
Thomas AA, Ernstoff MS, Fadul CE (2012). Immunotherapy
for the treatment of glioblastoma. Cancer J 18: 59–68.
Thomas AA, Brennan CW, DeAngelis LM et al. (2014).
Emerging therapies for glioblastoma. JAMA Neurol 71:
1437–1444.
Turcan S, Rohle D, Goenka A et al. (2012). IDH1 mutation is
sufficient to establish the glioma hypermethylator pheno-
type. Nature 483: 479–483.
van Breemen MS, Rijisman RM, Taphoorn MJ et al. (2009).
Efficacy of anti-epileptic drugs in patients with gliomas
and seizures. J Neurol 256: 1519–1526.
Verhaak RG, Hoadley KA, Purdom E et al. (2010). Integrated
genomic analysis identifies clinically relevant subtypes of
glioblastoma characterized by abnormalities in PDGFRA,
IDH1, EGFR, and NF1. Cancer Cell 17: 98–110.
Wang R, Chadalavada K, Wilshire J et al. (2010).
Glioblastoma stem-like cells give rise to tumour endothe-
lium. Nature 468: 829–833.
Warrens AN, Birch R, Collett D et al. (2012). Advising poten-
tial recipients on the use of organs from donors with pri-
mary central nervous system tumors. Transplantation 93:
348–353.
Watson CJ, Roberts R, Wright KA et al. (2010). How safe is it
to transplant organs from deceased donors with primary
intracranial malignancy? An analysis of UK Registry data.
Am J Transplant 10: 1437–1444.
Weber MA, Zoubaa S, Schlieter M et al. (2006). Diagnostic
performance of spectroscopic and perfusion MRI for dis-
tinction of brain tumors. Neurology 66: 1899–1906.
Weller M, Stupp R, Reifenberger G et al. (2010). MGMT pro-
moter methylation in malignant gliomas: ready for person-
alized medicine? Nat Rev Neurol 6: 39–51.
Weller M, Cloughesy T, Perry JR et al. (2013). Standards of
care for treatment of recurrent glioblastoma – are we there
yet? Neuro Oncol 15: 4–27.
Weller M, van den Bent M, Hopkins K et al. (2014). EANO
guideline for the diagnosis and treatment of anaplastic gli-
omas and glioblastoma. Lancet Oncol 15: e395–e403.
Weller M, Wick W, Aldape K et al. (2015a). Glioma. Nat Rev
Dis Primers.
Weller M, Tabatabai G, Kastner B et al. (2015b). MGMT pro-
moter methylation is a strong prognostic biomarker for
benefit from dose-intensified temozolomide rechallenge
in progressive glioblastoma: the DIRECTOR trial. Clin
Cancer Res 21: 2057–2064.
Wen PY, Macdonald DR, Reardon DA et al. (2010). Updated
response assessment criteria for high-grade gliomas:
response assessment in neuro-oncology working group.
J Clin Oncol 28: 1963–1972.
Wen P, Reardon D, Phuphanich S et al. (2014a). A randomized
double blind placebo-controlled phase 2 trial of dendritic
cell (DC) vaccine ICT-107 following standard treatment
in newly diagnosed patients with GBM. Neuro Oncol 16:
v8–v22.
 GLIOBLASTOMA
Wen PY, Chang SM, Lamborn KR et al. (2014b). Phase I/II
study of erlotinib and temsirolimus for patients with recur-
rent malignant gliomas: North American Brain Tumor
Consortium trial 04-02. Neuro Oncol 16: 567–578.
Wick W, Platten M (2014). CMV infection and glioma, a
highly controversial concept struggling in the clinical
arena. Neuro Oncol 16: 332–333.
Wick W, Menn O, Meisner C et al. (2005). Pharmacotherapy
of epileptic seizures in glioma patients: who, when, why
and how long? Onkologie 28: 391–396.
Wick W, Puduvalli VK, Chamberlain MC et al. (2010). Phase
III study of enzastaurin compared with lomustine in the
treatment of recurrent intracranial glioblastoma. J Clin
Oncol 28: 1168–1174.
Wick W, Platten M, Meisner C et al. (2012). Temozolomide
chemotherapy alone versus radiotherapy alone for malig-
nant astrocytoma in the elderly: the NOA-08 randomised,
phase 3 trial. Lancet Oncol 13: 707–715.
397
Wick W, Gorlia T, van den Bent M et al. (2014). Radiation
therapy and concurrent plus adjuvant temsirolimus (CCI-
779) versus chemoirradiation with temozolomide in newly
diagnosed glioblastoma without methylation of the MGMT
gene promoter. J Clin Oncol 32: 5s.
Wilson CB (1979). Current concepts in cancer: brain tumors.
N Engl J Med 300: 1469–1471.
Wolchok JD, Kluger H, Callahan MK et al. (2013). Nivolumab
plus ipilimumab in advanced melanoma. N Engl J Med 369:
122–133.
Yan H, Parsons DW, Jing G et al. (2009). IDH1 and IDH2
mutations in gliomas. N Engl J Med 360: 765–773.
Yan K, Yang K, Rich JN (2013). The evolving landscape of
glioblastoma stem cells. Curr Opin Neurol 26: 701–707.
Yuile P, Dent O, Cook R et al. (2006). Survival of glioblastoma
patients related to presenting symptoms, brain site and
treatment variables. J Clin Neurosci 13: 747–751.