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The n e w e ng l a n d j o u r na l of m e dic i n e

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, alignant gliomas account for approximately 70% of the 22,500
Department of Neurology, Brigham and new cases of malignant primary brain tumors that are diagnosed in adults
Women’s Hospital; and the Center for
Neuro-Oncology, Dana−Farber Cancer In- in the United States each year.1-3 Although relatively uncommon, malig-
stitute — both in Boston. Address reprint nant gliomas are associated with disproportionately high morbidity and mortality.
requests to Dr. Wen at the Center for Despite optimal treatment, the median survival is only 12 to 15 months for patients
Neuro-­Oncology, Dana−Farber/Brigham
and Women’s Cancer Center, SW430D, with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently,
44 Binney St., Boston, MA 02115, or at there have been important advances in our understanding of the molecular patho- genesis of malignant gliomas and progress in treating them. This review summa-
N Engl J Med 2008;359:492-507. rizes the diagnosis and management of these tumors in adults and highlights some
Copyright © 2008 Massachusetts Medical Society. areas under investigation.


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 glioblasto-
ma 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 Li−Fraumeni syndrome (germ-line p53
mutations associated with an increased risk of several cancers), and Turcot’s syn-
drome (intestinal polyposis and brain tumors).10 However, most familial cases have

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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 typ-
ically occur in patients older than 50 years of age
PATHOL O GIC A L FE AT UR E S and are characterized by EGFR amplification and
mutations, loss of heterozygosity of chromosome
Malignant gliomas are histologically heteroge- 10q, deletion of the phosphatase and tensin ho-
neous and invasive tumors that are derived from mologue on chromosome 10 (PTEN), and p16 de-
glia. 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 astro-
tures 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 tumor-
sidered malignant gliomas. Anaplastic astrocy- suppressor gene,23 overexpression of the platelet-
tomas are characterized by increased cellularity, derived growth factor receptor (PDGFR), abnor-
nuclear atypia, and mitotic activity. Glioblastomas malities in the p16 and retinoblastoma (Rb)
also contain areas of microvascular proliferation, pathways, and loss of heterozygosity of chromo-
necrosis, or both (Fig. 1 and 2). Uncommon glio- some 10q.18,24 Secondary glioblastomas have tran-
blastoma 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 re-
mas with oligodendroglial features, which may be spond differently to targeted molecular therapies.
associated with a better prognosis than standard High-grade oligodendrogliomas are character-
glioblastomas.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 low-
oligodendrogli­omas and oligoastrocytomas (WHO grade to anaplastic oligodendroglioma is associ-
grade II), and anaplastic oligodendrogliomas and ated with defects in PTEN, Rb, p53, and cell-
anaplastic oligoastrocytomas (WHO grade III) cycle pathways.1
(Fig. 1). All of these tumors may contain perinu-
clear 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 sig-
Malignant gliomas typically contain both neo- naling involve EGFR and PDGFR (Fig. 3).18 Am-
plastic 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 approximate-
come. 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 amplifica-
of 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
MOL ECUL A R PATHO GENE SIS through 7).14,18 This characteristic variant has
become an important therapeutic target for ki-
Recently, 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 ex-
malignant 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 fre-
mulation of genetic aberrations and the deregu- quently expressed in gliomas, creating an auto-
lation of growth-factor signaling pathways (Fig. 1 crine loop that stimulates proliferation of the

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The n e w e ng l a n d j o u r na l of m e dic i n e

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

Olig2 expression (100%) Olig2 expression (100%) Olig2 expression (100%)

P53 mutated (>65%) EGFR amplified (~40%) LOH 1p, 4q, 19q
PDGFA/PDGFR-α overexpressed (~60%) EGFR overexpressed (~60%) EGFR overexpressed
EGFR mutated (~20–30%) PDGF/PDGFR overexpressed
MDM2 amplified (~10%)
Low-Grade Astrocytoma (5–10 yr)*
MDM2 overexpressed (>50%)
(WHO Grade II) Low-Grade Oligodendroglioma (5–10 yr)*
LOH 10q (~70%)
LOH 19q (~50%) (WHO Grade II)
P16Ink4a/P14ARF loss (~30%)
RB mutated (~25%) P16Ink4a/P14ARF loss
PTEN mutated (~40%)
CDK4 amplified (15%) RB mutated (~65%)
PI3K mutated/amplified (~20%)
MDM2 overexpressed (10%) p53 mutated
RB mutated
P16Ink4a/P14ARF loss (4%) PTEN loss
VEGF overexpressed
LOH 11p (~30%) LOH 9p, 10q
Anaplastic Astrocytoma (2–3 yr)* CDK4/EGFR/MYC amplified
(WHO Grade III) VEGF overexpressed
LOH 10q (~70%)
DCC loss (~50%) Anaplastic Oligodendroglioma (3–5 yr)*
PDGFR-α amplified (~10%)
(WHO Grade III)
PTEN mutated (~10%)
PI3K mutated/amplified (~10%)
VEGF overexpressed
Secondary Glioblastoma (12–15 mo)* Primary Glioblastoma (12–15 mo)*
(WHO Grade IV) (WHO Grade IV)

Figure 1. Pathways in the Development of Malignant Gliomas.

Genetic and chromosomal alterations involved ICMin the development of the three main types of malignant gliomas (primary and secondary
glioblastomas and anaplastic oligodendroglioma)
REG F are shown.1 of 5
Oligodendrocyte transcription factor
3rd 2 (Olig2) (blue) and vascular endo­
thelial growth factor (VEGF) (red) are expressed
CASE in all high-grade gliomas. Median lengths
Revised of survival (asterisks) are shown. A slash
EMaildeleted in colorectalLine
indicates one or the other or both. DCC denotes 4-C EGFR epidermal
carcinoma, SIZE growth factor receptor, LOH loss of
heterozygosity, MDM2 murine double minuteEnon 2, PDGF platelet-derivedH/Tgrowth H/T
factor, PDGFR platelet-derived growth factor receptor,
Combo 39p6
PI3K phosphatidylinositol 3-kinase, PTEN phosphatase and tensin homologue, and RB retinoblastoma.
Figure has been redrawn and type has been reset.
Please check carefully.

tumor.18 Growth factor–receptor

JOB: 35905 signaling, through important role in the normal development of the
ISSUE: 7-31-08
intermediate signal-transduction generators, re- nervous system by promoting the proliferation of
sults in the activation of transcriptional programs multipotent stem cells. Other developmental path-
for survival, proliferation, invasion, and angio- ways that contribute to the biologic features of
genesis. Common signal-transduction pathways gliomas are those involving sonic hedgehog, wing-
activated by these growth factors are the Ras–­ less, Notch, CXC chemokine receptor 4 (CXCR4),
mitogen-activated protein (MAP) kinase path- and bone morphogenetic proteins.19 In addition,
way, which is involved in proliferation and cell- oligodendrocyte transcription factor 2 (Olig2),
cycle progression, and the phosphatidylinositol a developmentally regulated, lineage-restricted
3-kinase (PI3K)–Akt–mammalian target of rapa­ neural transcription factor, is a universal marker
mycin (mTOR) pathways, which are involved in the of diffuse gliomas and stem cells that may be
inhibition of apoptosis and cellular proliferation a prerequisite for early transformation.30 Drugs
(Fig. 3).18 PTEN, a tumor-suppressor gene that neg- that target these pathways are under active in-
atively regulates the PI3K pathway, is inactivated vestigation as treatment for gliomas.
in 40 to 50% of patients with glio­blastomas.18,27
Many of the above pathways lead to the up- Role of Stem Cells in Pathogenesis
regulation of vascular endothelial growth factor and Resistance to Therapy
(VEGF) and angiogenesis.28,29 EGFR, PDGFR, and Although the genetic and signaling pathways in-
VEGF-receptor (VEGFR) pathways also play an volved in the development of malignant gliomas

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Figure 2. Pathological Features of Malignant Gliomas.

Panels A and B show the histologic appearance of a glioblastoma, characterized by nuclear pleomorphism, dense cellu-
larity, and pseudopalisading necrosis (asterisk) (Panel A, hematoxylin and eosin) as well as vascular endothelial prolifera-
tion (asterisk) and mitotic figures (arrows)
ICM (Panel
AUTHORB, hematoxylin
wen and eosin).RETAKE
Panels C and
1st D show the histologic features
of an anaplastic oligodendroglioma, including the typical
REG F FIGURE perinuclear halo (“fried egg”)2nd
2a-f appearance (Panel C, hematoxy-
lin and eosin) and diffuse Olig2 staining
CASE(Panel D, brown color). The proliferation
TITLE index
can be quantified by immunohis-
tochemical analysis with the use of Ki67 staining (Panel E, black color), 4-C
Line and heterogeneous EGFR amplification by colori-
Enon than
metric in situ hybridization showing more two signals
mst (brown SIZE
ARTIST: H/T spots in nuclei)
H/T in almost all tumor cells (Panel F).
(Courtesy of Ali G. Saad, M.D., Department Combo
of Pathology, Brigham and Women’s33p9Hospital.)
Figure has been redrawn and type has been reset.
Please check carefully.
have been relatively well characterized, the cellu- differentiation into distinctive mature cell types.31
JOB: 35905 ISSUE: 7-31-08
lar origins of these tumors are unknown. The There is increasing evidence that neural stem cells,
adult nervous system harbors neural stem cells or related progenitor cells, can be transformed into
that are capable of self-renewal, proliferation, and cancer stem cells and give rise to malignant gliomas

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by escaping the mechanisms that control prolif-

Figure 3 (facing page). Major Signaling Pathways
eration and programmed differentiation (Fig. in Malignant Gliomas and the Corresponding Targeted
4).32-36 These stem cells are identified by several Agents in Development for Glioblastoma.
immunocytochemical markers, such as CD133, RTK inhibitors that target epidermal growth factor
a glycoprotein also known as prominin 1.26,32,35,37 (EGF) receptor include gefitinib, erlotinib, lapatinib,
Although stem cells account for only a minority BIBW2992, and vandetanib; those that target platelet-
derived growth factor (PDGF) receptor include ima-
of the cells within malignant gliomas, they ap-
tinib, dasatinib, and tandutinib; those that target vas-
pear to be critical for generating these tumors.36,38 cular endothelial growth factor (VEGF) receptor
Recent studies suggest that glioma stem cells pro- include cediranib, pazopanib, sorafenib, sunitinib, vata-
duce VEGF and promote angiogenesis in the tu- lanib, vandetanib, and XL184. EGF receptor antibodies
mor microenvironment.39 In addition, tumor stem include cetuximab and panitumumab. Farnesyl trans-
ferase inhibitors include lonafarnib and tipifarnib;
cells appear to require a vascular niche for opti-
HDAC inhibitors include depsipeptide, vorinostat, and
mal function.40 These observations raise the pos- LBH589; PI3K inhibitors include BEZ235 and XL765;
sibility that antiangiogenic therapy may inhibit mTOR inhibitors include sirolimus, temsirolimus,
the functioning of glioma stem cells. everolimus, and deforolimus; and VEGF receptor inhib-
There is growing evidence that glioma stem itors include bevacizumab, aflibercept (VEGF-trap),
and CT-322. Growth factor ligands include EGF, PDGF,
cells may contribute to the resistance of malig-
IGF, TGF, HGF/SF, VEGF, and FGF. Stem-cell pathways
nant gliomas to standard treatments (Fig. 4). include SHH, wingless family, and Notch. Akt denotes
Radioresistance in stem cells generally results murine thymoma viral oncogene homologue (also
from the preferential activation of DNA-damage- known as protein kinase B), CDK cyclin-dependent ki-
response pathways,41 whereas chemoresistance re- nase, ERK extracellular signal-regulated kinase, FGF fi-
broblast growth factor, FTI farnesyl transferase inhibi-
sults partly from the overexpression of O6-meth­
tors, GDP guanine diphosphate, Grb 2 growth factor
ylguanine−DNA methyltransferase (MGMT), the receptor-bound protein 2, GTP guanine triphosphate,
up-regulation of multidrug resistance genes, and HDAC histone deacetylase, HGF/SF hepatocyte growth
the inhibition of apoptosis.42-44 Therapeutic strat- factor/scatter factor, IGF insulin-like growth factor,
egies that effectively target stem cells and over- MEK mitogen-activated protein kinase kinase, mTOR
mammalian target of rapamycin, NF1 neurofibromin 1,
come their resistance to treatment will be neces-
PIP2 phosphatidylinositol (4,5) biphosphate, PIP3
sary if malignant gliomas are to be completely phosphatidylinositol 3,4,5-triphosphate, PI3K phos-
eradicated (Fig. 4). A better understanding of the phatidylinositol 3-kinase, PKC protein kinase C, PLC
biologic differences between normal and cancer phospholipase C, PTEN phosphatase and tensin ho-
stem cells will be required to develop selective mologue, RAF v-raf 1 murine leukemia viral oncogene
homologue 1, RAS rat sarcoma viral oncogene homo-
therapies that spare normal brain cells.
logue, RTK receptor tyrosine kinase inhibitor, SHH
sonic hedgehog, SOS son of sevenless, Src sarcoma
DI AGNOSIS (Schmidt-Ruppin A-2) viral oncogene homologue, TGF
transforming growth factor family, and TSC1 and 2 tu-
Clinical Presentation berous sclerosis gene 1 and 2. Red text denotes inhibi-
tors. Data are from Sathornsumetee et al.,3 Furnari
Patients with malignant gliomas may present with
et al.,18 Chi and Wen,20 and Sathornsumetee et al.21
a variety of symptoms, including headaches, sei-
zures, focal neurologic deficits, confusion, mem-
typically show a heterogeneously enhancing mass
ory loss, and personality changes. Although the
with surrounding edema. Glioblastomas frequent-
classic headaches that are suggestive of increased
ly have central areas of necrosis and more exten-
intracranial pressure are most severe in the morn-
ing and may wake the patient from sleep, many sive peritumoral edema than that associated with
anaplastic gliomas.45 Functional MRI may help
patients experience headaches that are indistin-
guishable from tension headaches. When severe,define the relationship of speech and motor ar-
eas to the tumor and aid in the planning of sur-
the headaches may be associated with nausea and
vomiting. gery. Diffusion-weighted imaging, diffusion ten-
sor imaging, dynamic contrast-enhanced MRI to
Imaging measure vessel permeability, and perfusion im-
The 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 line peak (reflecting increased membrane turn-
the levels of metabolites and may help differenti- over) and a decrease in the N-acetyl aspartate peak
ate a tumor from necrosis or benign lesions. In (reflecting decreased neuronal cellularity), as com-
patients with malignant gliomas, this imaging pared with the findings in unaffected areas of the
technique typically shows an increase in the cho- 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, oligodendro-
glia, 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-flu- are performed in the first month after radiothera-
oro-l-thymidine, 11C-methionine, and 3,4-dihy- py show increased enhancement.48 In 50% of these
droxy-6-18F-fluoro-l-phenylalanine is being eval- cases, the increased enhancement reflects a tran-
uated for its usefulness in diagnosis and in mon- sient increase in vessel permeability as a result of
­itoring the response to therapy.47 radiotherapy, a phenomenon termed “pseudopro-
In up to 40% of cases, the MRI studies that gression,” which improves with time.48 Differen-

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tiating this transient effect from true progres- of 20 to 30%.49,53 The risk of intratumoral hem-
sion of the cancer can be challenging initially, orrhage associated with anticoagulation therapy
even with advanced imaging techniques. in patients with gliomas who have venous throm-
boembolism is low,49,54 whereas inferior vena cava
T R E ATMEN T filters are associated with high complication
rates.55 Unless a patient with malignant glioma
General Medical Management and venous thromboembolism has an intracere-
Much 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-molecular-
itumoral 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 an- Patients 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 malig-
the routine use of antiepileptic drugs in patients nant gliomas involves surgical resection when fea-
with 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 eliminat-
quently used to treat peritumoral edema. Cush- ed surgically because of their infiltrative nature,
ing’s 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 pro-
with brain tumors who receive corticosteroids are vides tissue for histologic diagnosis and molecu-
at increased risk for Pneumocystis jiroveci pneumoni- lar studies. Advances such as MRI-guided neuro-
tis, and prophylactic antibiotic therapy should be navigation, intraoperative MRI, functional MRI,
considered,49 although a recent meta-analysis did intraoperative mapping,60 and fluorescence-guid-
not 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 sur-
treatment with corticosteroids, including osteo- vival is controversial, but patients who undergo
porosis and compression fractures, are becoming extensive resection probably have a modest sur-
increasingly 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 inoper-
plements, and bisphosphonates, should be con- able tumors that are located in critical areas.
sidered. Novel therapies such as corticotropin- Radiotherapy is the mainstay of treatment for
releasing 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
need for corticosteroids.49,52 a range of 7 to 12 months.63,64 Conventional ra-
Patients with malignant gliomas are at in- diotherapy consists of 60 Gy of partial-field exter-
creased 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 radio-

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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 Maximal surgical resection, with the following options after surgery (no ac-
grade III) cepted standard treatment): radiotherapy, plus concomitant and adjuvant
TMZ or adjuvant TMZ alone†
Anaplastic oligodendrogliomas Maximal surgical resection, with the following options after surgery (no ac-
and anaplastic oligoastrocy- cepted standard treatment): radiotherapy alone, TMZ or PCV with or with-
tomas (WHO grade III) out 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 procar-
bazine, 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 ad-
ministered 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 apy results in a modest increase in survival (a 6 to
site.65 Strategies to increase the radiation dose to 10% increase in the 1-year survival rate).75,76
the tumor with the use of brachytherapy 66 and The European Organisation for Research and
stereotactic radiosurgery 67,68 have failed to im- Treatment of Cancer (EORTC) and the National
prove survival. Newer chemotherapeutic agents,69 Cancer Institute of Canada (NCIC) conducted a
targeted molecular agents,20 and antiangiogenic phase III trial comparing radiotherapy alone (60 Gy
agents70 may enhance the effectiveness of radio- over a period of 6 weeks) with radiotherapy and
therapy. concomitant treatment with temozolomide (75 mg
Patients who are older than 70 years of age have per square meter of body-surface area per day
a worse prognosis than younger patients and rep- for 6 weeks), followed by adjuvant temozolomide
resent a particular challenge. Among these pa- therapy (150 to 200 mg per square meter per day
tients, radiotherapy produces a modest benefit in for 5 days every 28 days for 6 cycles), in patients
median survival (29.1 weeks) as compared with with newly diagnosed glioblastomas.64 As reported
supportive care (16.9 weeks).71 Since older pa- by Stupp et al., the combination of radiotherapy
tients often tolerate radiotherapy less well than and temozolomide had an acceptable side-effect
younger patients, an abbreviated course of radio- profile and, as compared with radiotherapy alone,
therapy (40 Gy in 15 fractions over a period of increased the median survival (14.6 months vs.
3 weeks)72 or chemotherapy with temozolomide 12.1 months, P<0.001).64 In addition, the survival
(an oral alkylating agent with good penetration rate at 2 years among the patients who received
of the blood–brain barrier) alone73 may be con- radiotherapy and temozolomide was significantly
sidered, since the outcomes with these approach- greater than the rate among the patients who
es are similar to the outcomes with conventional received radiotherapy alone (26.5% vs. 10.4%),64
radiotherapy regimens. establishing radiotherapy with concomitant and
Chemotherapy is assuming an increasingly im- adjuvant temozolomide as a useful combination
portant role in the treatment of malignant gliomas. for newly diagnosed glioblastomas.
Although early studies of adjuvant chemotherapy MGMT is an important repair enzyme that con-
for malignant gliomas with the use of nitroso­ tributes to resistance to temozolomide. In a com-
ureas failed to show a benefit,63,74 two meta- panion study to the EORTC–NCIC study reported
analyses have suggested that adjuvant chemother­ by Stupp et al., tumor specimens from the pa-

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tients were examined for epigenetic silencing of 19q,79 mediated by an unbalanced translocation
the MGMT gene.15 MGMT promoter methylation of 19p to 1q,80 occurs in 61 to 89% of patients with
silences the gene, thus decreasing DNA repair ac- anaplastic oligodendrogliomas and 14 to 20% of
tivity and increasing the susceptibility of the tu- patients with anaplastic oligoastrocytomas. Tu-
mor cells to temozolomide. Patients with glioblas- mors in patients with the 1p and 19q codeletion
toma and MGMT promoter methylation (45% of the are particularly sensitive to chemotherapy with
total) who were treated with temozolomide had PCV — procarbazine, lomustine (CCNU), and vin-
a median survival of 21.7 months and a 2-year cristine — with response rates of up to 100%, as
survival rate of 46%. In contrast, patients without compared with response rates of 23 to 31% among
MGMT promoter methylation who were treated patients without the deletion of chromosomes 1p
with temozolomide had a significantly shorter and 19q.81,82 The reason for the increased chemo-
median survival of only 12.7 months and a 2-year sensitivity of tumors in patients with the 1p and
survival rate of 13.8%.15 Currently, temozolomide 19q codeletion is unclear. One study suggested
is used in the treatment of glioblastomas regard- that 1p loss is associated with decreased levels of
less of MGMT promoter methylation status. How- stathmin and an increased sensitivity to nitroso­
ever, if the importance of MGMT promoter methy- ureas.83 The status of chromosomes 1p and 19q,
lation is confirmed by the results of an ongoing rather than standard histologic assessment, is now
study by the Radiation Therapy Oncology Group used as an eligibility criterion in studies involv-
(RTOG 0525), patients with unfavorable MGMT ing patients with anaplastic oligodendrogliomas
methylation status may be selected for other and anaplastic oligoastrocytomas, reflecting a par-
treatments in future investigations. Studies of adigm shift in the design of clinical trials for pa-
dose-intensive temozolomide regimens to deplete tients with these tumors.
MGMT and of combinations of temozolomide Two large phase III studies of PCV chemother-
with inhibitors of MGMT, such as O6-benzylgua- apy with radiotherapy, as compared with radio-
nine, and inhibitors of other repair enzymes, such therapy alone, in patients with newly diagnosed
as poly-(ADP-ribose)-polymerase, are in progress. anaplastic oligodendrogliomas or anaplastic oli-
Another chemotherapeutic approach involves goastrocytomas, have been reported.84,85 In both
the implantation of biodegradable polymers con- studies, the addition of chemotherapy to radio-
taining carmustine (Gliadel Wafers, MGI Pharma) therapy increased the time to tumor progression
into the tumor bed after resection of the tumor. by 10 to 12 months but did not improve overall
The aim of treatment with these polymers, which survival (median, 3.4 and 4.9 years).84,85 The fail-
release carmustine gradually over the course of ure of chemotherapy to increase survival may be
several weeks, is to kill residual tumor cells. In partly explained by the fact that patients who ini-
a randomized, placebo-controlled trial that inves- tially received radiotherapy alone subsequently re-
tigated the use of these polymers in patients with ceived chemotherapy when they had a relapse, so
newly diagnosed malignant gliomas, median sur- that most patients in both groups eventually re-
vival increased from 11.6 months to 13.9 months ceived chemotherapy. In both studies, patients
(P = 0.03).77 This survival advantage was main- with the codeletion of 1p and 19q had improved
tained at 2 and 3 years.78 survival as compared with those without the code-
letion of 1p and 19q. Although most studies
Therapy for Anaplastic Gliomas involving patients with anaplastic oligodendro-
Anaplastic astrocytomas are treated with radio- gliomas or anaplastic oligoastrocytomas were con-
therapy and either concurrent and adjuvant temo- ducted with PCV chemotherapy, temozolomide is
zolomide (as for glioblastomas) or adjuvant temo- likely to have similar activity and less toxicity79;
zolomide alone. Currently, there are no findings however, studies directly comparing the two regi-
from controlled trials that support the use of con- mens have not been performed.
current temozolomide in patients with anaplastic
astrocytomas. Therapy for Recurrent Malignant Gliomas
Anaplastic oligodendrogliomas and anaplas- Despite optimal treatment, nearly all malignant
tic oligoastrocytomas are an important subgroup gliomas eventually recur. For glioblastomas, the
of malignant gliomas that are generally more re- median time to progression after treatment with
sponsive to therapy than are pure astrocytic tu- radiotherapy and temozolomide is 6.9 months.64
mors.79 A codeletion of chromosomes 1p and If the tumor is symptomatic from mass effect, re-

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The n e w e ng l a n d j o u r na l of m e dic i n e

operation may be indicated (Table 1). However, sur- have poor penetration across the blood−tumor bar-
gery performed in selected patients results in only rier. There has been considerable interest in iden-
limited prolongation of survival.86 tifying molecular features of the tumor that pre-
The usefulness of radiotherapy for recurrent dict a response, so that patients who are most
malignant gliomas is controversial.87 Although likely to benefit can be selected for a particular
some reports have suggested that fractionated ste- treatment. EGFR inhibitors appear to be more ef-
reotactic reirradiation88 and stereotactic radiosur- fective in patients who have tumors with EGFRvIII
gery68 may be beneficial, selection bias may have mutations and intact PTEN than in patients who
influenced these results. do not have these molecular changes99; patients
The value of conventional chemotherapy for re- who have tumors with increased activity of the
current malignant gliomas is modest. In general, PI3K–Akt pathway, as indicated by an increase in
chemotherapy is more effective for anaplastic phosphorylated Akt, generally do not have a re-
gliomas than for glioblastomas.79,87 Temozolo- sponse.100 Current experimental strategies to in-
mide was evaluated in a phase II study involving crease the effectiveness of targeted molecular ther-
patients with recurrent anaplastic gliomas who apies include the use of a single agent targeted
had previously been treated with nitrosoureas; the against several kinases, combinations of agents
study showed a 35% response rate. The 6-month that inhibit complementary targets such as EGFR
rate of progression-free survival was 46%,89 com- and mTOR (Table 2 and Fig. 5A through 5D), and
paring favorably with the 31% rate of progression- targeted agents combined with radiotherapy and
free survival at 6 months for therapies that were chemotherapy.3,18,20,21
reported to be ineffective.90 In contrast, temozolo-
mide has only limited activity in patients with Antiangiogenic Agents
recurrent glioblastomas (response rate, 5.4%; Malignant gliomas are among the most vascular
6-month rate of progression-free survival, 21%).91 of human tumors,18 making them especially at-
Other chemotherapeutic agents that are used for tractive targets for angiogenesis inhibitors.29 Al-
recurrent gliomas include nitrosoureas, carbo- though older antiangiogenic agents such as tha-
platin, procarbazine, irinotecan, and etoposide. lidomide had only modest activity,101 newer and
Carmustine wafers have modest activity, increas- more potent angiogenesis inhibitors show prom-
ing the median survival by approximately 8 weeks ising activity. In preliminary studies, treatment
in patients with recurrent glioblastomas.92 with the combination of bevacizumab and irino-
tecan was associated with a low incidence of hem-
IN V E S T IG AT IONA L THER A PIE S orrhage and response rates of 57 to 63% among
patients with malignant gliomas (Fig. 5E through
Targeted Molecular Therapies 5H).102,103 Some of the improvement that is seen
The improved understanding of the molecular on radiographic images may be artifactual, caused
pathogenesis of malignant gliomas has allowed by reduced vascular permeability and decreased
a more rational use of targeted molecular thera- contrast enhancement as a result of the inhibi-
pies (Fig. 3).18,20,21 Particular interest has focused tion of VEGF. However, this regimen also has
on inhibitors that target receptor tyrosine kinases antitumor activity, as evidenced by the fact that it
such as EGFR,93 PDGFR,94 and VEGFR,52 as well increased the 6-month rate of progression-free
as on signal-transduction inhibitors targeting survival to 46% among patients with recurrent
mTOR,95,96 farnesyltransferase,97 and PI3K (Ta- glioblastomas,102,103 as compared with a 6-month
ble 2). Single agents have only modest activity, rate of progression-free survival of 21% for pa-
with response rates of 0 to 15% and no prolonga- tients who were receiving treatment with temozo-
tion of 6-month progression-free survival.3,20,21 lomide.91 Recently, a large, randomized phase II
These disappointing results are due to several fac- trial of bevacizumab alone and bevacizumab with
tors. Most malignant gliomas have coactivation of irinotecan was completed. Preliminary results con-
multiple tyrosine kinases,98 as well as redundant firmed the safety of bevacizumab and showed an
signaling pathways, thus limiting the activity of increase in the 6-month rate of progression-free
single agents. In addition, many of these agents survival to 35.1% for patients receiving bevacizu­

502 n engl j med 359;5  july 31, 2008

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Medical Progress

Table 2. Selected Investigational Treatments for Malignant Gliomas.*

Type of Treatment Example

Convection-enhanced surgical delivery of pharmacologic 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-αvβ5 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,
FTI inhibitors Tipifarnib, lonafarnib
HDAC inhibitors Vorinostat, depsipeptide, LBH589
HSP90 inhibitors ATI3387
Met XL184
mTOR inhibitors Everolimus, sirolimus, temsirolimus, deforolimus
PI3K inhibitors BEZ235, XL765
PKCβ Enzastaurin
PDGFR inhibitors Dasatinib, imatinib, tandutinib
Proteasome Bortezomib
Raf Sorafenib
Src Dasatinib
TGF-β AP12009
Combination therapies Erlotinib plus temsirolimus, gefitinib plus everolimus,
gefitinib plus sirolimus, sorafenib plus temsirolimus,
erlotinib, or tipifarnib, pazopanib plus lapatinib
Dendritic cell and EGFRvIII peptide vaccines DCVax, CDX-110
Monoclonal antibodies antibody
Gene therapy
Other therapies

* 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-methylguanine−DNA methyltransferase, mTOR mammalian target of rapamycin, PARP poly (ADP-ribose)
polymerase, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PKCβ protein kinase C β,
TGF transforming growth factor, TMZ temozolomide, and VEGFR vascular endothelial growth factor receptor.

n engl j med 359;5  july 31, 2008 503

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The n e w e ng l a n d j o u r na l 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 combi-
nation of erlotinib (an inhibitor of epidermal growth factor receptor [EGFR]) and sirolimus (an inhibitor of the mam-
malian target of rapamycin [mTOR]). ICM AUTHORimages
T1-weighted wen obtained after the administration
RETAKE 1st of gadolinium show a re-
duction in the size of the enhancingREG tumor pretreatment image (Panel A) 2nd
from the 5a-h
F FIGURE to the image obtained 2 months
CASE 3rd
after treatment (Panel B), with fluid-attenuated
TITLE inversion recovery (FLAIR) Revised
studies showing a reduction of edema
from the pretreatment image (Panel C) to the post-treatment Lineimage4-C (Panel D). Panels E through H show MRI scans
Enon whoARTIST: mst with SIZE
of a recurrent glioblastoma in a patient was treated H/Ta combination
H/T of bevacizumab and irinotecan. T1-
FILL Combo 33p9
weighted images obtained after the administration of gadolinium show a reduction in the size of the enhancing tu-
mor from the image obtained before treatment AUTHOR,(Panel E)PLEASE NOTE: obtained 7 months after treatment (Panel F)
to the image
and an associated reduction of edemaFigure from has
thebeen redrawn andFLAIR
pretreatment type has been (Panel
image reset. G) to the post-treatment FLAIR
Please check carefully.
image (Panel H).
JOB: 35905 ISSUE: 7-31-08

mab alone and 50.2% for patients receiving the cross the blood−tumor barrier more effectively,
combination of bevacizumab and irinotecan.104 gene therapy,105 peptide and dendritic-cell vac­
A phase II trial of the pan-VEGFR inhibitor ce­ cines,106 radiolabeled monoclonal antibodies
dira­nib in patients with recurrent glioblastomas against the extracellular matrix protein tena­
showed response rates in excess of 50% and pro- scin,107 synthetic chlorotoxins (131I-TM-601),108
longation of the 6-month rate of progression-free and infusion of radiolabeled drugs and target­
survival to approximately 26%.52 These agents also ed toxins into the tumor and surrounding brain
decrease peritumoral edema, potentially allowing by means of convection-enhanced delivery (Ta-
for a reduction in corticosteroid requirements. ble 2).109
Since antiangiogenic agents may have synergistic
activity with radiotherapy, there is increasing in- PRO GNOS T IC FAC T OR S
terest in combining them with radiotherapy and
temozolomide in patients with newly diagnosed The most important adverse prognostic factors
glioblastomas.29,70 As noted previously, glioma
in patients with malignant gliomas are advanced
stem cells produce VEGF39 and require a vascular
age, histologic features of glioblastoma, poor Kar-
niche for optimal function.40 Antiangiogenic agents
nofsky performance status, and unresectable tu-
may therefore also target glioma stem cells. mor.110 There are ongoing efforts to identify bio-
logic 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 opti-
gliomas include chemotherapeutic agents that mal therapy.15,16,82

504 n engl j med 359;5  july 31, 2008

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Medical Progress

Supported by grants from the National Institutes of Health

SUM M A R Y (U01 CA062407, to Dr. Wen; and KO8 CA1240804, to Dr. Kesari),
a Sontag Foundation Distinguished Scientist Grant (to Dr. Kesari),
Recently, there has been important progress in and research support from the Elizabeth Atkins and Will Kraft
the treatment of malignant gliomas111 and in our Brain Tumor Research Funds (to Dr. Wen) and the John Kenney
Brain Tumor Research Fund (to Dr. Kesari).
understanding of the molecular pathogenesis of Dr. Wen reports receiving speaking fees from Schering-
these tumors and the critical role that stem cells Plough, serving as a consultant for AngioChem, and receiving
research funding from Exelixis, Schering-Plough, Genentech,
play in their development and resistance to treat- GlaxoSmithKline, Amgen, AstraZeneca, and Celgene. Dr. Kesari
ment. As our understanding of the molecular cor- reports receiving consulting fees from Bristol–Myers Squibb,
relates of response improves, it may be possible speaking fees from Enzon, and research funding from Adnexus.
No other potential conflict of interest relevant to this article was
to select the most appropriate therapies on the reported.
basis of the patient’s tumor genotype. These ad- We thank Drs. Andrew Norden and Elizabeth Claus for help-
ful comments.
vances provide real opportunities for the develop- This article is dedicated to the memories of Elizabeth Atkins,
ment of effective therapies for malignant gliomas. Will Kraft, and John Kenney.

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New England Journal of Medicine


Malignant Gliomas in Adults

Malignant Gliomas in Adults . The institution in Dr. Wen’s address

(page 492) should have read ``Dana–Farber/Brigham and Women’s
Cancer Center.´´ In Table 2 (page 503), the ``Dendritic cell and
EGFRvIII peptide vaccines´´ row should have included the following
entry: DCVax, CDX-110. The article has been corrected on the Jour-
nal’s Web site at

N Engl J Med 2008;359:877-a

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