Nej MR A 0708126

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review article
Medical Progress
Malignant Gliomas in Adults

Patrick Y. Wen, M.D., and Santosh Kesari, M.D., Ph.D.
From the Division of Neuro-Oncology,

Department of Neurology, Brigham and
Womens Hospital; and the Center for
Neuro-Oncology, DanaFarber Cancer Institute both in Boston. Address reprint
requests to Dr. Wen at the Center for
Neuro-Oncology, DanaFarber/Brigham
and Womens Cancer Center, SW430D,
44 Binney St., Boston, MA 02115, or at
pwen@partners.org.
N Engl J Med 2008;359:492-507.
Copyright 2008 Massachusetts Medical Society.
alignant gliomas account for approximately 70% of the 22,500

new cases of malignant primary brain tumors that are diagnosed in adults
in the United States each year.1-3 Although relatively uncommon, malignant gliomas are associated with disproportionately high morbidity and mortality.
Despite optimal treatment, the median survival is only 12 to 15 months for patients
with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently,
there have been important advances in our understanding of the molecular pathogenesis of malignant gliomas and progress in treating them. This review summarizes the diagnosis and management of these tumors in adults and highlights some
areas under investigation.
EPIDEMIOL O GIC FE AT UR E S
The annual incidence of malignant gliomas is approximately 5 cases per 100,000
people.1,2 Each year, more than 14,000 new cases are diagnosed in the United
States.1,2 Glioblastomas account for approximately 60 to 70% of malignant gliomas,
anaplastic astrocytomas for 10 to 15%, and anaplastic oligodendrogliomas and
anaplastic oligoastrocytomas for 10%; less common tumors such as anaplastic
ependymomas and anaplastic gangliogliomas account for the rest.1,2 The incidence
of these tumors has increased slightly over the past two decades, especially in the
elderly,4 primarily as a result of improved diagnostic imaging. Malignant gliomas
are 40% more common in men than in women and twice as common in whites as
in blacks.2 The median age of patients at the time of diagnosis is 64 years in the
case of glioblastomas and 45 years in the case of anaplastic gliomas.2,4
No underlying cause has been identified for the majority of malignant gliomas.
The only established risk factor is exposure to ionizing radiation.4 Evidence for an
association with head injury, foods containing N-nitroso compounds, occupational
risk factors, and exposure to electromagnetic fields is inconclusive.4 Although there
has been some concern about an increased risk of gliomas in association with the
use of cellular telephones,5 the largest studies have not demonstrated this.4,6,7 There
is suggestive evidence of an association between immunologic factors and gliomas.
Patients with atopy have a reduced risk of gliomas,8 and patients with glioblastoma who have elevated IgE levels appear to live longer than those with normal levels.9
The importance of these associations is unclear. Gene polymorphisms that affect
detoxification, DNA repair, and cell-cycle regulation have also been implicated in
the development of gliomas.4
Approximately 5% of patients with malignant gliomas have a family history of
gliomas. Some of these familial cases are associated with rare genetic syndromes,
such as neurofibromatosis types 1 and 2, the LiFraumeni syndrome (germ-line p53
mutations associated with an increased risk of several cancers), and Turcots syndrome (intestinal polyposis and brain tumors).10 However, most familial cases have
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n engl j med 359;5 www.nejm.org july 31, 2008
The New England Journal of Medicine

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Copyright 2008 Massachusetts Medical Society. All rights reserved.
Medical Progress
no identified genetic cause. Recently, an interna- and 3).18,22 Glioblastomas can be separated into
tional consortium, GLIOGENE, was established two main subtypes on the basis of biologic and
to study the genetic basis of familial gliomas.11 genetic differences.18,22 Primary glioblastomas typically occur in patients older than 50 years of age
and are characterized by EGFR amplification and
PATHOL O GIC A L FE AT UR E S
mutations, loss of heterozygosity of chromosome
Malignant gliomas are histologically heteroge- 10q, deletion of the phosphatase and tensin honeous and invasive tumors that are derived from mologue on chromosome 10 (PTEN), and p16 deglia. The World Health Organization (WHO) clas- letion. Secondary glioblastomas are manifested in
sifies astrocytomas on the basis of histologic fea- younger patients as low-grade or anaplastic astrotures into four prognostic grades: grade I (pilo- cytomas and transform over a period of several
cytic astrocytoma), grade II (diffuse astrocytoma), years into glioblastomas. These tumors, which are
grade III (anaplastic astrocytoma), and grade IV much less common than primary glioblastomas,
(glioblastoma).1 Grade III and IV tumors are con- are characterized by mutations in the p53 tumorsidered malignant gliomas. Anaplastic astrocy- suppressor gene,23 overexpression of the platelettomas are characterized by increased cellularity, derived growth factor receptor (PDGFR), abnornuclear atypia, and mitotic activity. Glioblastomas malities in the p16 and retinoblastoma (Rb)
also contain areas of microvascular proliferation, pathways, and loss of heterozygosity of chromonecrosis, or both (Fig. 1 and 2). Uncommon glio- some 10q.18,24 Secondary glioblastomas have tranblastoma variants include gliosarcomas, which scriptional patterns and aberrations in the DNA
contain a prominent sarcomatous element; giant- copy number that differ markedly from those of
cell glioblastomas, which have multinucleated primary glioblastomas.18,22 Despite their genetic
giant cells; small-cell glioblastomas, which are differences, primary and secondary glioblastomas
associated with amplification of the epidermal are morphologically indistinguishable and respond
growth factor receptor (EGFR); and glioblasto- similarly to conventional therapy, but they may remas with oligodendroglial features, which may be spond differently to targeted molecular therapies.
associated with a better prognosis than standard
High-grade oligodendrogliomas are characterglioblastomas.1,12 Oligodendrogliomas are divided ized by the loss of chromosomes 1p and 19q (in
by the WHO into two grades: well-differentiated 50 to 90% of patients).1 Progression from lowoligodendrogliomas and oligoastrocytomas (WHO grade to anaplastic oligodendroglioma is associgrade II), and anaplastic oligodendrogliomas and ated with defects in PTEN, Rb, p53, and cellanaplastic oligoastrocytomas (WHO grade III) cycle pathways.1
(Fig. 1). All of these tumors may contain perinuclear halos (Fig. 2C) and a delicate network of Deregulated Growth Factor Signaling
branching blood vessels (chicken-wire pattern).1 The most common defects in growth-factor sigMalignant gliomas typically contain both neo- naling involve EGFR and PDGFR (Fig. 3).18 Amplastic and stromal tissues, which contribute to plification of EGFR occurs almost exclusively in
their histologic heterogeneity and variable out- primary glioblastomas and is seen in approximatecome. Molecular studies such as gene-expression ly 40 to 50% of patients with that type of tumor.
profiling potentially allow for better classification About half of the tumors with EGFR amplificaof these tumors and separation of the tumors tion express a constitutively autophosphorylated
into different prognostic groups.13-17
variant of EGFR, known as EGFRvIII, that lacks
the extracellular ligand-binding domain (exons 2
through 7).14,18 This characteristic variant has
MOL ECUL A R PATHO GENE SIS
become an important therapeutic target for kiRecently, there has been important progress in our nase inhibitors, immunotoxins, and peptide vac
understanding of the molecular pathogenesis of cines.3,18 Recently, activating mutations in the exmalignant gliomas, and especially the importance tracellular domain of EGFR have been identified.25
of cancer stem cells.18,19 Malignant transforma- PDGF signaling is a key regulator of glial devel
tion in gliomas results from the sequential accu- opment,26 and both ligand and receptors are fremulation of genetic aberrations and the deregu- quently expressed in gliomas, creating an autolation of growth-factor signaling pathways (Fig. 1 crine loop that stimulates proliferation of the

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Cell-of-Origin: Differentiated Glial or Stem or Progenitor Cells

Olig2 expression (100%)
P53 mutated (>65%)
PDGFA/PDGFR- overexpressed (~60%)
Low-Grade Astrocytoma (510 yr)*

(WHO Grade II)
LOH 19q (~50%)
RB mutated (~25%)
CDK4 amplified (15%)
MDM2 overexpressed (10%)
P16Ink4a/P14ARF loss (4%)
LOH 11p (~30%)
Anaplastic Astrocytoma (23 yr)*

(WHO Grade III)

EGFR amplified (~40%)
LOH 1p, 4q, 19q
EGFR overexpressed (~60%)
EGFR overexpressed
EGFR mutated (~2030%)
PDGF/PDGFR overexpressed
MDM2 amplified (~10%)
MDM2 overexpressed (>50%)
Low-Grade Oligodendroglioma (510 yr)*
LOH 10q (~70%)
(WHO Grade II)
P16Ink4a/P14ARF loss (~30%)
P16Ink4a/P14ARF loss
PTEN mutated (~40%)
RB mutated (~65%)
PI3K mutated/amplified (~20%)
p53 mutated
RB mutated
PTEN loss
VEGF overexpressed
LOH 9p, 10q
CDK4/EGFR/MYC amplified
VEGF overexpressed
LOH 10q (~70%)

DCC loss (~50%)
PDGFR- amplified (~10%)
PTEN mutated (~10%)
PI3K mutated/amplified (~10%)
VEGF overexpressed
Secondary Glioblastoma (1215 mo)*

(WHO Grade IV)
Anaplastic Oligodendroglioma (35 yr)*

(WHO Grade III)
Primary Glioblastoma (1215 mo)*

(WHO Grade IV)
Figure 1. Pathways in the Development of Malignant Gliomas.

1st
RETAKE
AUTHOR: Wen
ICMin the development of the three main types of malignant gliomas (primary and secondary
Genetic and chromosomal alterations involved
2nd
FIGURE:
5
REG F are
glioblastomas and anaplastic oligodendroglioma)
shown.1 of
Oligodendrocyte
transcription factor
2 (Olig2) (blue) and vascular endo
3rd
CASE in all high-grade gliomas. Median lengths
thelial growth factor (VEGF) (red) are expressed
Revised of survival (asterisks) are shown. A slash
4-C EGFR epidermal
indicates one or the other or both. DCC denotes
carcinoma,
growth factor receptor, LOH loss of
EMaildeleted in colorectalLine
SIZE
ARTIST: ts
heterozygosity, MDM2 murine double minuteEnon
2, PDGF platelet-derivedH/T
growth H/T
factor, PDGFR platelet-derived growth factor receptor,
Combo
39p6
PI3K phosphatidylinositol 3-kinase, PTEN phosphatase and tensin homologue, and RB retinoblastoma.
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
JOB: 35905
tumor.18 Growth factorreceptor
signaling, through
intermediate signal-transduction generators, results in the activation of transcriptional programs
for survival, proliferation, invasion, and angiogenesis. Common signal-transduction pathways
activated by these growth factors are the Ras
mitogen-activated protein (MAP) kinase pathway, which is involved in proliferation and cellcycle progression, and the phosphatidylinositol
3-kinase (PI3K)Aktmammalian target of rapa
mycin (mTOR) pathways, which are involved in the
inhibition of apoptosis and cellular proliferation
(Fig. 3).18 PTEN, a tumor-suppressor gene that negatively regulates the PI3K pathway, is inactivated
in 40 to 50% of patients with glioblastomas.18,27
Many of the above pathways lead to the upregulation of vascular endothelial growth factor
(VEGF) and angiogenesis.28,29 EGFR, PDGFR, and
VEGF-receptor (VEGFR) pathways also play an
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important
role in the normal development of the
nervous system by promoting the proliferation of
multipotent stem cells. Other developmental pathways that contribute to the biologic features of
gliomas are those involving sonic hedgehog, wingless, Notch, CXC chemokine receptor 4 (CXCR4),
and bone morphogenetic proteins.19 In addition,
oligodendrocyte transcription factor 2 (Olig2),
a developmentally regulated, lineage-restricted
neural transcription factor, is a universal marker
of diffuse gliomas and stem cells that may be
a prerequisite for early transformation.30 Drugs
that target these pathways are under active investigation as treatment for gliomas.
Role of Stem Cells in Pathogenesis

and Resistance to Therapy
Although the genetic and signaling pathways involved in the development of malignant gliomas

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*
*
C
Figure 2. Pathological Features of Malignant Gliomas.

Panels A and B show the histologic appearance of a glioblastoma, characterized by nuclear pleomorphism, dense cellularity, and pseudopalisading necrosis (asterisk) (Panel A, hematoxylin and eosin) as well as vascular endothelial prolifera1st D show the histologic features
wen
AUTHOR
ICM (Panel
tion (asterisk) and mitotic figures (arrows)
B, hematoxylin
and eosin).RETAKE
Panels C and
REG F FIGURE
2a-f
of an anaplastic oligodendroglioma, including
the typical
perinuclear halo (fried egg)2nd
appearance (Panel C, hematoxy3rd
CASE(Panel
lin and eosin) and diffuse Olig2 staining
D, brown color). The proliferation
index
can be quantified by immunohisTITLE
Revised
EMail
tochemical analysis with the use of Ki67
staining (Panel E, black
color), 4-C
and heterogeneous EGFR amplification by coloriLine
SIZE
Enon than
ARTIST:
mst (brown
metric in situ hybridization showing more
two signals
in nuclei)
in almost all tumor cells (Panel F).
H/T spots
H/T
FILL
Combo
(Courtesy of Ali G. Saad, M.D., Department
of Pathology, Brigham
and Womens33p9
Hospital.)
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
have been relatively well characterized, the celluJOB: 35905

lar origins of these tumors are unknown. The
adult nervous system harbors neural stem cells
that are capable of self-renewal, proliferation, and
differentiation into distinctive mature cell types.31

ISSUE: 7-31-08
There is increasing evidence that neural stem cells,
or related progenitor cells, can be transformed into
cancer stem cells and give rise to malignant gliomas

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by escaping the mechanisms that control proliferation and programmed differentiation (Fig.
4).32-36 These stem cells are identified by several
immunocytochemical markers, such as CD133,
a glycoprotein also known as prominin 1.26,32,35,37
Although stem cells account for only a minority
of the cells within malignant gliomas, they appear to be critical for generating these tumors.36,38
Recent studies suggest that glioma stem cells produce VEGF and promote angiogenesis in the tumor microenvironment.39 In addition, tumor stem
cells appear to require a vascular niche for optimal function.40 These observations raise the possibility that antiangiogenic therapy may inhibit
the functioning of glioma stem cells.
There is growing evidence that glioma stem
cells may contribute to the resistance of malignant gliomas to standard treatments (Fig. 4).
Radioresistance in stem cells generally results
from the preferential activation of DNA-damageresponse pathways,41 whereas chemoresistance results partly from the overexpression of O6-meth
ylguanineDNA methyltransferase (MGMT), the
up-regulation of multidrug resistance genes, and
the inhibition of apoptosis.42-44 Therapeutic strategies that effectively target stem cells and overcome their resistance to treatment will be necessary if malignant gliomas are to be completely
eradicated (Fig. 4). A better understanding of the
biologic differences between normal and cancer
stem cells will be required to develop selective
therapies that spare normal brain cells.
DI AGNOSIS
Clinical Presentation
Patients with malignant gliomas may present with

a variety of symptoms, including headaches, seizures, focal neurologic deficits, confusion, memory loss, and personality changes. Although the
classic headaches that are suggestive of increased
intracranial pressure are most severe in the morning and may wake the patient from sleep, many
patients experience headaches that are indistinguishable from tension headaches. When severe,
the headaches may be associated with nausea and
vomiting.
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Figure 3 (facing page). Major Signaling Pathways

in Malignant Gliomas and the Corresponding Targeted
Agents in Development for Glioblastoma.
RTK inhibitors that target epidermal growth factor
(EGF) receptor include gefitinib, erlotinib, lapatinib,
BIBW2992, and vandetanib; those that target plateletderived growth factor (PDGF) receptor include imatinib, dasatinib, and tandutinib; those that target vascular endothelial growth factor (VEGF) receptor
include cediranib, pazopanib, sorafenib, sunitinib, vatalanib, vandetanib, and XL184. EGF receptor antibodies
include cetuximab and panitumumab. Farnesyl transferase inhibitors include lonafarnib and tipifarnib;
HDAC inhibitors include depsipeptide, vorinostat, and
LBH589; PI3K inhibitors include BEZ235 and XL765;
mTOR inhibitors include sirolimus, temsirolimus,
everolimus, and deforolimus; and VEGF receptor inhibitors include bevacizumab, aflibercept (VEGF-trap),
and CT-322. Growth factor ligands include EGF, PDGF,
IGF, TGF, HGF/SF, VEGF, and FGF. Stem-cell pathways
include SHH, wingless family, and Notch. Akt denotes
murine thymoma viral oncogene homologue (also
known as protein kinase B), CDK cyclin-dependent kinase, ERK extracellular signal-regulated kinase, FGF fibroblast growth factor, FTI farnesyl transferase inhibitors, GDP guanine diphosphate, Grb 2 growth factor
receptor-bound protein 2, GTP guanine triphosphate,
HDAC histone deacetylase, HGF/SF hepatocyte growth
factor/scatter factor, IGF insulin-like growth factor,
MEK mitogen-activated protein kinase kinase, mTOR
mammalian target of rapamycin, NF1 neurofibromin 1,
PIP2 phosphatidylinositol (4,5) biphosphate, PIP3
phosphatidylinositol 3,4,5-triphosphate, PI3K phosphatidylinositol 3-kinase, PKC protein kinase C, PLC
phospholipase C, PTEN phosphatase and tensin homologue, RAF v-raf 1 murine leukemia viral oncogene
homologue 1, RAS rat sarcoma viral oncogene homologue, RTK receptor tyrosine kinase inhibitor, SHH
sonic hedgehog, SOS son of sevenless, Src sarcoma
(Schmidt-Ruppin A-2) viral oncogene homologue, TGF
transforming growth factor family, and TSC1 and 2 tuberous sclerosis gene 1 and 2. Red text denotes inhibitors. Data are from Sathornsumetee et al.,3 Furnari
et al.,18 Chi and Wen,20 and Sathornsumetee et al.21
typically show a heterogeneously enhancing mass

with surrounding edema. Glioblastomas frequently have central areas of necrosis and more extensive peritumoral edema than that associated with
anaplastic gliomas.45 Functional MRI may help
define the relationship of speech and motor areas to the tumor and aid in the planning of surgery. Diffusion-weighted imaging, diffusion tensor imaging, dynamic contrast-enhanced MRI to
Imaging
measure vessel permeability, and perfusion imThe diagnosis of malignant gliomas is usually aging to measure relative cerebral blood volume
suggested by magnetic resonance imaging (MRI) are increasingly used as diagnostic aids and as a
or computed tomography. These imaging studies means of monitoring the response to therapy.46
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Proton magnetic resonance spectroscopy detects

the levels of metabolites and may help differentiate a tumor from necrosis or benign lesions. In
patients with malignant gliomas, this imaging
technique typically shows an increase in the cho-
line peak (reflecting increased membrane turnover) and a decrease in the N-acetyl aspartate peak
(reflecting decreased neuronal cellularity), as compared with the findings in unaffected areas of the
brain.45,46 Positron-emission tomography that uses

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Figure 4. Resistance Mechanisms in Glioma Cells.

Normal neural stem cells self-renew and give rise to multipotential progenitor cells that form neurons, oligodendroglia, and astrocytes. Glioma stem cells arise from the transformation of either neural stem cells or progenitor cells
(red) or, less likely, from differentiation of a oligodendrocytes or astrocytes (thin red arrows) and lead to malignant
gliomas. Glioma stem cells are relatively resistant to standard treatments such as radiation and chemotherapy and
lead to regrowth of the tumor after treatment. Therapies directed at stem cells can deplete these cells and poten
tially lead to more durable tumor regression (blue).
isotopes such as 18F-fluorodeoxyglucose, 18F-fluoro-l-thymidine, 11C-methionine, and 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine is being evaluated for its usefulness in diagnosis and in monitoring the response to therapy.47
In up to 40% of cases, the MRI studies that
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are performed in the first month after radiotherapy show increased enhancement.48 In 50% of these
cases, the increased enhancement reflects a transient increase in vessel permeability as a result of
radiotherapy, a phenomenon termed pseudoprogression, which improves with time.48 Differen-

Medical Progress
tiating this transient effect from true progres- of 20 to 30%.49,53 The risk of intratumoral hemsion of the cancer can be challenging initially, orrhage associated with anticoagulation therapy
even with advanced imaging techniques.
in patients with gliomas who have venous thromboembolism is low,49,54 whereas inferior vena cava
filters are associated with high complication
T R E ATMEN T
rates.55 Unless a patient with malignant glioma
General Medical Management
and venous thromboembolism has an intracereMuch of the care of patients with malignant bral hemorrhage or other contraindications, it is
gliomas involves general medical management. generally safe to provide anticoagulation therapy
The most common problems include seizures, per- for the venous thromboembolism. Low-molecularitumoral edema, venous thromboembolism, fa- weight heparin may be more effective and safer
tigue, and cognitive dysfunction.49 Patients who than warfarin.56
present with seizures should be treated with anPatients with malignant gliomas frequently ex
tiepileptic drugs. Since antiepileptic drugs that perience fatigue and may benefit from treatment
induce hepatic cytochrome P-450 enzymes, such with modafinil or methylphenidate.57 Methyl
as phenytoin and carbamazepine, increase the me- phenidate may also help abulia, and donepezil58
tabolism of many chemotherapeutic agents, anti- and memantine may reduce memory loss, although
epileptic drugs that do not induce these enzymes, evidence supporting these approaches remains
such as levetiracetam, are generally preferred. The limited. Depression is underdiagnosed in patients
use of prophylactic antiepileptic drugs in patients with malignant gliomas, and antidepressants and
with malignant gliomas who have never had a psychiatric support are often invaluable.59
seizure is controversial. The American Academy of
Neurology issued a practice guideline indicating Specific Therapy for Newly Diagnosed
that there is no evidence that prophylactic anti- Malignant Gliomas
epileptic drugs are beneficial and advises against The standard therapy for newly diagnosed maligthe routine use of antiepileptic drugs in patients nant gliomas involves surgical resection when feawith brain tumors who have not had seizures.50 sible, radiotherapy, and chemotherapy (Table 1).
Corticosteroids such as dexamethasone are fre- Malignant gliomas cannot be completely eliminatquently used to treat peritumoral edema. Cush- ed surgically because of their infiltrative nature,
ings syndrome and corticosteroid myopathy may but patients should undergo maximal surgical
develop in patients who require prolonged treat- resection whenever possible. Surgical debulking
ment with high doses of corticosteroids. Patients reduces the symptoms from mass effect and prowith brain tumors who receive corticosteroids are vides tissue for histologic diagnosis and molecuat increased risk for Pneumocystis jiroveci pneumoni- lar studies. Advances such as MRI-guided neurotis, and prophylactic antibiotic therapy should be navigation, intraoperative MRI, functional MRI,
considered,49 although a recent meta-analysis did intraoperative mapping,60 and fluorescence-guidnot show a benefit from this approach.51 As the ed surgery61 have improved the safety of surgery
rate of survival among patients with malignant and increased the extent of resection that can be
glioma improves, long-term complications from achieved. The value of surgery in prolonging surtreatment with corticosteroids, including osteo- vival is controversial, but patients who undergo
porosis and compression fractures, are becoming extensive resection probably have a modest surincreasingly evident, and preventive measures, vival advantage.60-62 Stereotactic biopsies should
such as treatment with vitamin D, calcium sup- be performed only in patients who have inoperplements, and bisphosphonates, should be con- able tumors that are located in critical areas.
Radiotherapy is the mainstay of treatment for
sidered. Novel therapies such as corticotropinreleasing factor, bevacizumab (a humanized VEGF malignant gliomas. The addition of radiotherapy
monoclonal antibody), and VEGFR inhibitors de- to surgery increases survival among patients with
crease peritumoral edema and may reduce the glioblastomas from a range of 3 to 4 months to
a range of 7 to 12 months.63,64 Conventional raneed for corticosteroids.49,52
Patients with malignant gliomas are at in- diotherapy consists of 60 Gy of partial-field extercreased risk for venous thromboembolism from nal-beam irradiation delivered 5 days per week
leg and pelvic veins, with a cumulative incidence in fractions of 1.8 to 2.0 Gy. After standard radion engl j med 359;5 www.nejm.org july 31, 2008

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Table 1. Summary of Current Treatments for Malignant Gliomas.*

Type of Tumor
Therapy
Newly diagnosed tumors

Glioblastomas (WHO grade IV)
Maximal surgical resection, plus radiotherapy, plus concomitant and adjuvant

TMZ or carmustine wafers (Gliadel)
Anaplastic astrocytomas (WHO

grade III)
Maximal surgical resection, with the following options after surgery (no accepted standard treatment): radiotherapy, plus concomitant and adjuvant
TMZ or adjuvant TMZ alone
Anaplastic oligodendrogliomas
and anaplastic oligoastrocytomas (WHO grade III)
Maximal surgical resection, with the following options after surgery (no accepted standard treatment): radiotherapy alone, TMZ or PCV with or without radiotherapy afterward, radiotherapy plus concomitant and adjuvant
TMZ, or radiotherapy plus adjuvant TMZ
Recurrent tumors
Reoperation in selected patients, carmustine wafers (Gliadel), conventional

chemotherapy (e.g., lomustine, carmustine, PCV, carboplatin, irinotecan,
etoposide), bevacizumab plus irinotecan, experimental therapies
* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 PCV denotes procarbazine, lomustine (CCNU), and vincristine, and TMZ temozolomide.
Radiotherapy is administered at a dose of 60 Gy given in 30 fractions over a period of 6 weeks. Concomitant TMZ is administered at a dose of 75 mg per square meter of body-surface area per day for 42 days with radiotherapy. Beginning
4 weeks after radiotherapy, adjuvant TMZ is administered at a dose of 150 mg per square meter per day on days 1 to
5 of the first 28-day cycle, followed by 200 mg per square meter per day on days 1 to 5 of each subsequent 28-day cycle,
if the first cycle was well tolerated.
PCV therapy consists of lomustine (CCNU), 110 mg per square meter, on day 1; procarbazine, 60 mg per square meter,
on days 8 to 21; and vincristine, 1.5 mg per square meter (maximum dose, 2 mg), on days 8 and 29.
therapy, 90% of the tumors recur at the original

site.65 Strategies to increase the radiation dose to
the tumor with the use of brachytherapy66 and
stereotactic radiosurgery67,68 have failed to improve survival. Newer chemotherapeutic agents,69
targeted molecular agents,20 and antiangiogenic
agents70 may enhance the effectiveness of radiotherapy.
Patients who are older than 70 years of age have
a worse prognosis than younger patients and represent a particular challenge. Among these patients, radiotherapy produces a modest benefit in
median survival (29.1 weeks) as compared with
supportive care (16.9 weeks).71 Since older patients often tolerate radiotherapy less well than
younger patients, an abbreviated course of radiotherapy (40 Gy in 15 fractions over a period of
3 weeks)72 or chemotherapy with temozolomide
(an oral alkylating agent with good penetration
of the bloodbrain barrier) alone73 may be considered, since the outcomes with these approaches are similar to the outcomes with conventional
radiotherapy regimens.
Chemotherapy is assuming an increasingly important role in the treatment of malignant gliomas.
Although early studies of adjuvant chemotherapy
for malignant gliomas with the use of nitroso
ureas failed to show a benefit,63,74 two metaanalyses have suggested that adjuvant chemother
500
apy results in a modest increase in survival (a 6 to

10% increase in the 1-year survival rate).75,76
The European Organisation for Research and
Treatment of Cancer (EORTC) and the National
Cancer Institute of Canada (NCIC) conducted a
phase III trial comparing radiotherapy alone (60 Gy
over a period of 6 weeks) with radiotherapy and
concomitant treatment with temozolomide (75 mg
per square meter of body-surface area per day
for 6 weeks), followed by adjuvant temozolomide
therapy (150 to 200 mg per square meter per day
for 5 days every 28 days for 6 cycles), in patients
with newly diagnosed glioblastomas.64 As reported
by Stupp et al., the combination of radiotherapy
and temozolomide had an acceptable side-effect
profile and, as compared with radiotherapy alone,
increased the median survival (14.6 months vs.
12.1 months, P<0.001).64 In addition, the survival
rate at 2 years among the patients who received
radiotherapy and temozolomide was significantly
greater than the rate among the patients who
received radiotherapy alone (26.5% vs. 10.4%),64
establishing radiotherapy with concomitant and
adjuvant temozolomide as a useful combination
for newly diagnosed glioblastomas.
MGMT is an important repair enzyme that contributes to resistance to temozolomide. In a companion study to the EORTCNCIC study reported
by Stupp et al., tumor specimens from the pa-

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tients were examined for epigenetic silencing of

the MGMT gene.15 MGMT promoter methylation
silences the gene, thus decreasing DNA repair activity and increasing the susceptibility of the tumor cells to temozolomide. Patients with glioblastoma and MGMT promoter methylation (45% of the
total) who were treated with temozolomide had
a median survival of 21.7 months and a 2-year
survival rate of 46%. In contrast, patients without
MGMT promoter methylation who were treated
with temozolomide had a significantly shorter
median survival of only 12.7 months and a 2-year
survival rate of 13.8%.15 Currently, temozolomide
is used in the treatment of glioblastomas regardless of MGMT promoter methylation status. However, if the importance of MGMT promoter methylation is confirmed by the results of an ongoing
study by the Radiation Therapy Oncology Group
(RTOG 0525), patients with unfavorable MGMT
methylation status may be selected for other
treatments in future investigations. Studies of
dose-intensive temozolomide regimens to deplete
MGMT and of combinations of temozolomide
with inhibitors of MGMT, such as O6-benzylguanine, and inhibitors of other repair enzymes, such
as poly-(ADP-ribose)-polymerase, are in progress.
Another chemotherapeutic approach involves
the implantation of biodegradable polymers containing carmustine (Gliadel Wafers, MGI Pharma)
into the tumor bed after resection of the tumor.
The aim of treatment with these polymers, which
release carmustine gradually over the course of
several weeks, is to kill residual tumor cells. In
a randomized, placebo-controlled trial that investigated the use of these polymers in patients with
newly diagnosed malignant gliomas, median survival increased from 11.6 months to 13.9 months
(P=0.03).77 This survival advantage was maintained at 2 and 3 years.78
Therapy for Anaplastic Gliomas
Anaplastic astrocytomas are treated with radiotherapy and either concurrent and adjuvant temozolomide (as for glioblastomas) or adjuvant temozolomide alone. Currently, there are no findings
from controlled trials that support the use of concurrent temozolomide in patients with anaplastic
astrocytomas.
Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas are an important subgroup
of malignant gliomas that are generally more responsive to therapy than are pure astrocytic tumors.79 A codeletion of chromosomes 1p and
19q,79 mediated by an unbalanced translocation

of 19p to 1q,80 occurs in 61 to 89% of patients with
anaplastic oligodendrogliomas and 14 to 20% of
patients with anaplastic oligoastrocytomas. Tumors in patients with the 1p and 19q codeletion
are particularly sensitive to chemotherapy with
PCV procarbazine, lomustine (CCNU), and vincristine with response rates of up to 100%, as
compared with response rates of 23 to 31% among
patients without the deletion of chromosomes 1p
and 19q.81,82 The reason for the increased chemosensitivity of tumors in patients with the 1p and
19q codeletion is unclear. One study suggested
that 1p loss is associated with decreased levels of
stathmin and an increased sensitivity to nitroso
ureas.83 The status of chromosomes 1p and 19q,
rather than standard histologic assessment, is now
used as an eligibility criterion in studies involving patients with anaplastic oligodendrogliomas
and anaplastic oligoastrocytomas, reflecting a paradigm shift in the design of clinical trials for patients with these tumors.
Two large phase III studies of PCV chemotherapy with radiotherapy, as compared with radiotherapy alone, in patients with newly diagnosed
anaplastic oligodendrogliomas or anaplastic oligoastrocytomas, have been reported.84,85 In both
studies, the addition of chemotherapy to radiotherapy increased the time to tumor progression
by 10 to 12 months but did not improve overall
survival (median, 3.4 and 4.9 years).84,85 The failure of chemotherapy to increase survival may be
partly explained by the fact that patients who initially received radiotherapy alone subsequently received chemotherapy when they had a relapse, so
that most patients in both groups eventually received chemotherapy. In both studies, patients
with the codeletion of 1p and 19q had improved
survival as compared with those without the codeletion of 1p and 19q. Although most studies
involving patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas were conducted with PCV chemotherapy, temozolomide is
likely to have similar activity and less toxicity79;
however, studies directly comparing the two regimens have not been performed.
Therapy for Recurrent Malignant Gliomas
Despite optimal treatment, nearly all malignant

gliomas eventually recur. For glioblastomas, the
median time to progression after treatment with
radiotherapy and temozolomide is 6.9 months.64
If the tumor is symptomatic from mass effect, re-

501
The
operation may be indicated (Table 1). However, surgery performed in selected patients results in only
limited prolongation of survival.86
The usefulness of radiotherapy for recurrent
malignant gliomas is controversial.87 Although
some reports have suggested that fractionated stereotactic reirradiation88 and stereotactic radiosurgery68 may be beneficial, selection bias may have
influenced these results.
The value of conventional chemotherapy for recurrent malignant gliomas is modest. In general,
chemotherapy is more effective for anaplastic
gliomas than for glioblastomas.79,87 Temozolomide was evaluated in a phase II study involving
patients with recurrent anaplastic gliomas who
had previously been treated with nitrosoureas; the
study showed a 35% response rate. The 6-month
rate of progression-free survival was 46%,89 comparing favorably with the 31% rate of progressionfree survival at 6 months for therapies that were
reported to be ineffective.90 In contrast, temozolomide has only limited activity in patients with
recurrent glioblastomas (response rate, 5.4%;
6-month rate of progression-free survival, 21%).91
Other chemotherapeutic agents that are used for
recurrent gliomas include nitrosoureas, carboplatin, procarbazine, irinotecan, and etoposide.
Carmustine wafers have modest activity, increasing the median survival by approximately 8 weeks
in patients with recurrent glioblastomas.92
IN V E S T IG AT IONA L THER A PIE S

Targeted Molecular Therapies
The improved understanding of the molecular

pathogenesis of malignant gliomas has allowed
a more rational use of targeted molecular therapies (Fig. 3).18,20,21 Particular interest has focused
on inhibitors that target receptor tyrosine kinases
such as EGFR,93 PDGFR,94 and VEGFR,52 as well
as on signal-transduction inhibitors targeting
mTOR,95,96 farnesyltransferase,97 and PI3K (Table 2). Single agents have only modest activity,
with response rates of 0 to 15% and no prolongation of 6-month progression-free survival.3,20,21
These disappointing results are due to several factors. Most malignant gliomas have coactivation of
multiple tyrosine kinases,98 as well as redundant
signaling pathways, thus limiting the activity of
single agents. In addition, many of these agents
502
of
m e dic i n e
have poor penetration across the bloodtumor barrier. There has been considerable interest in identifying molecular features of the tumor that predict a response, so that patients who are most
likely to benefit can be selected for a particular
treatment. EGFR inhibitors appear to be more effective in patients who have tumors with EGFRvIII
mutations and intact PTEN than in patients who
do not have these molecular changes99; patients
who have tumors with increased activity of the
PI3KAkt pathway, as indicated by an increase in
phosphorylated Akt, generally do not have a response.100 Current experimental strategies to increase the effectiveness of targeted molecular therapies include the use of a single agent targeted
against several kinases, combinations of agents
that inhibit complementary targets such as EGFR
and mTOR (Table 2 and Fig. 5A through 5D), and
targeted agents combined with radiotherapy and
chemotherapy.3,18,20,21
Antiangiogenic Agents
Malignant gliomas are among the most vascular

of human tumors,18 making them especially attractive targets for angiogenesis inhibitors.29 Although older antiangiogenic agents such as thalidomide had only modest activity,101 newer and
more potent angiogenesis inhibitors show promising activity. In preliminary studies, treatment
with the combination of bevacizumab and irinotecan was associated with a low incidence of hemorrhage and response rates of 57 to 63% among
patients with malignant gliomas (Fig. 5E through
5H).102,103 Some of the improvement that is seen
on radiographic images may be artifactual, caused
by reduced vascular permeability and decreased
contrast enhancement as a result of the inhibition of VEGF. However, this regimen also has
antitumor activity, as evidenced by the fact that it
increased the 6-month rate of progression-free
survival to 46% among patients with recurrent
glioblastomas,102,103 as compared with a 6-month
rate of progression-free survival of 21% for patients who were receiving treatment with temozolomide.91 Recently, a large, randomized phase II
trial of bevacizumab alone and bevacizumab with
irinotecan was completed. Preliminary results confirmed the safety of bevacizumab and showed an
increase in the 6-month rate of progression-free
survival to 35.1% for patients receiving bevacizu

Medical Progress
Table 2. Selected Investigational Treatments for Malignant Gliomas.*

Type of Treatment
Example
Convection-enhanced surgical delivery of pharmacologic

agent
Cintredekin besudotox
Drugs to overcome resistance to TMZ

Dose-dense TMZ
MGMT inhibitors
O6-benzylguanine
PARP inhibitors
BSI-201, ABT-888
New chemotherapies
RTA744, ANG1005
Antiangiogenic therapies
Anti-v5 integrins
Cilengitide
Anti-hepatocyte growth factor
AMG-102
Anti-VEGF
Bevacizumab, aflibercept (VEGF-Trap)
Anti-VEGFR
Cediranib, pazopanib sorafenib, sunitinib, vandetinib,

vatalanib, XL184, CT-322
Other agents
Thalidomide
Targeted molecular therapies

Akt
Perifosine
EGFR inhibitors
Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab,

cetuximab
FTI inhibitors
Tipifarnib, lonafarnib
HDAC inhibitors
Vorinostat, depsipeptide, LBH589
HSP90 inhibitors
ATI3387
Met
XL184
mTOR inhibitors
Everolimus, sirolimus, temsirolimus, deforolimus
PI3K inhibitors
BEZ235, XL765
PKC
Enzastaurin
PDGFR inhibitors
Dasatinib, imatinib, tandutinib
Proteasome
Bortezomib
Raf
Sorafenib
Src
Dasatinib
TGF-
AP12009
Combination therapies
Erlotinib plus temsirolimus, gefitinib plus everolimus,

gefitinib plus sirolimus, sorafenib plus temsirolimus,
erlotinib, or tipifarnib, pazopanib plus lapatinib
Immunotherapies
Dendritic cell and EGFRvIII peptide vaccines
DCVax, CDX-110
Monoclonal antibodies
131I-anti-tenascin
antibody
Gene therapy
Other therapies
131I-TM-601
* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 EGFR denotes
epidermal growth factor receptor, FTI farnesyltransferase, HDAC histone deacetylase, HSP90 heat-shock protein 90,
MGMT O6-methylguanineDNA methyltransferase, mTOR mammalian target of rapamycin, PARP poly (ADP-ribose)
polymerase, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PKC protein kinase C ,
TGF transforming growth factor, TMZ temozolomide, and VEGFR vascular endothelial growth factor receptor.

503
The
of
m e dic i n e
Figure 5. MRI Scans Showing Responses to Targeted Agents.

Panels A through D show MRI scans in a patient with a recurrent malignant glioma who was treated with a combination of erlotinib (an inhibitor of epidermal growth factor receptor [EGFR]) and sirolimus (an inhibitor of the mamRETAKE
1st
wen obtained after the
AUTHORimages
ICM
malian target of rapamycin [mTOR]).
T1-weighted
administration
of gadolinium show a reF FIGURE
duction in the size of the enhancingREG
tumor
from the 5a-h
pretreatment image (Panel A) 2nd
to the image obtained 2 months
3rd
CASE
TITLE inversion recovery (FLAIR) Revised
after treatment (Panel B), with fluid-attenuated
studies showing a reduction of edema
EMail
from the pretreatment image (Panel C) to the post-treatment
(Panel D). Panels E through H show MRI scans
Lineimage4-C
SIZE
Enon who
ARTIST:
mst with
H/Ta combination
H/T
of a recurrent glioblastoma in a patient
was treated
of
bevacizumab and irinotecan. T1FILL
33p9
Combo
weighted images obtained after the administration of gadolinium show a reduction in the size of the enhancing tuNOTE: obtained 7 months after treatment (Panel F)
mor from the image obtained before treatment AUTHOR,
(Panel E)PLEASE
to the image
redrawn andFLAIR
type has
been (Panel
reset. G) to the post-treatment FLAIR
and an associated reduction of edemaFigure
from has
thebeen
pretreatment
image
image (Panel H).
JOB:
35905
mab alone and 50.2% for patients receiving the

combination of bevacizumab and irinotecan.104
A phase II trial of the pan-VEGFR inhibitor ce
diranib in patients with recurrent glioblastomas
showed response rates in excess of 50% and prolongation of the 6-month rate of progression-free
survival to approximately 26%.52 These agents also
decrease peritumoral edema, potentially allowing
for a reduction in corticosteroid requirements.
Since antiangiogenic agents may have synergistic
activity with radiotherapy, there is increasing interest in combining them with radiotherapy and
temozolomide in patients with newly diagnosed
glioblastomas.29,70 As noted previously, glioma
stem cells produce VEGF39 and require a vascular
niche for optimal function.40 Antiangiogenic agents
may therefore also target glioma stem cells.
ISSUE:
7-31-08
cross the bloodtumor barrier more effectively,

gene therapy,105 peptide and dendritic-cell vac
cines,106 radiolabeled monoclonal antibodies
against the extracellular matrix protein tena
scin,107 synthetic chlorotoxins (131I-TM-601),108
and infusion of radiolabeled drugs and target
ed toxins into the tumor and surrounding brain
by means of convection-enhanced delivery (Table 2).109
PRO GNOS T IC FAC T OR S
The most important adverse prognostic factors

in patients with malignant gliomas are advanced
age, histologic features of glioblastoma, poor Karnofsky performance status, and unresectable tumor.110 There are ongoing efforts to identify biologic and genetic alterations in the tumors that
Other Therapies
may provide additional prognostic information, as
Other investigational therapies for malignant well as guidance in making decisions about optigliomas include chemotherapeutic agents that mal therapy.15,16,82
504

Medical Progress
SUM M A R Y
Recently, there has been important progress in
the treatment of malignant gliomas111 and in our
understanding of the molecular pathogenesis of
these tumors and the critical role that stem cells
play in their development and resistance to treatment. As our understanding of the molecular correlates of response improves, it may be possible
to select the most appropriate therapies on the
basis of the patients tumor genotype. These advances provide real opportunities for the development of effective therapies for malignant gliomas.
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Supported by grants from the National Institutes of Health

(U01 CA062407, to Dr. Wen; and KO8 CA1240804, to Dr. Kesari),
a Sontag Foundation Distinguished Scientist Grant (to Dr. Kesari),
and research support from the Elizabeth Atkins and Will Kraft
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The

Malignant Gliomas in Adults

From the Division of Neuro-Oncology,

alignant gliomas account for approximately 70% of the 22,500

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

The New England Journal of Medicine

Cell-of-Origin: Differentiated Glial or Stem or Progenitor Cells

Low-Grade Astrocytoma (510 yr)*

Anaplastic Astrocytoma (23 yr)*

Olig2 expression (100%)

LOH 10q (~70%)

Secondary Glioblastoma (1215 mo)*

Anaplastic Oligodendroglioma (35 yr)*

Primary Glioblastoma (1215 mo)*

Figure 1. Pathways in the Development of Malignant Gliomas.

Role of Stem Cells in Pathogenesis

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

Figure 2. Pathological Features of Malignant Gliomas.

have been relatively well characterized, the celluJOB: 35905

differentiation into distinctive mature cell types.31

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

Patients with malignant gliomas may present with

Figure 3 (facing page). Major Signaling Pathways

typically show a heterogeneously enhancing mass

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

Proton magnetic resonance spectroscopy detects

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

Figure 4. Resistance Mechanisms in Glioma Cells.

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

The New England Journal of Medicine

Table 1. Summary of Current Treatments for Malignant Gliomas.*

Newly diagnosed tumors

Maximal surgical resection, plus radiotherapy, plus concomitant and adjuvant

Anaplastic astrocytomas (WHO

Reoperation in selected patients, carmustine wafers (Gliadel), conventional

therapy, 90% of the tumors recur at the original

apy results in a modest increase in survival (a 6 to

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

tients were examined for epigenetic silencing of

19q,79 mediated by an unbalanced translocation

Despite optimal treatment, nearly all malignant

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

IN V E S T IG AT IONA L THER A PIE S

The improved understanding of the molecular

Malignant gliomas are among the most vascular

n engl j med 359;5 www.nejm.org july 31, 2008

The New England Journal of Medicine

Table 2. Selected Investigational Treatments for Malignant Gliomas.*

Convection-enhanced surgical delivery of pharmacologic

Drugs to overcome resistance to TMZ

Anti-hepatocyte growth factor

Bevacizumab, aflibercept (VEGF-Trap)

Cediranib, pazopanib sorafenib, sunitinib, vandetinib,

Targeted molecular therapies

Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab,