Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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
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
492
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
n engl j med 359;5 www.nejm.org july 31, 2008
493
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
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
494
ISSUE: 7-31-08
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.
Although the genetic and signaling pathways involved in the development of malignant gliomas
Medical Progress
*
*
C
495
The
n e w e ng l a n d j o u r na l
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
of
m e dic i n e
Medical Progress
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
497
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
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
498
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
499
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Therapy
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
* 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.
Medical Progress
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
501
The
n e w e ng l a n d j o u r na l
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
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
Medical Progress
Example
Cintredekin besudotox
O6-benzylguanine
PARP inhibitors
BSI-201, ABT-888
New chemotherapies
RTA744, ANG1005
Antiangiogenic therapies
Anti-v5 integrins
Cilengitide
AMG-102
Anti-VEGF
Anti-VEGFR
Other agents
Thalidomide
Perifosine
EGFR inhibitors
FTI inhibitors
Tipifarnib, lonafarnib
HDAC inhibitors
HSP90 inhibitors
ATI3387
Met
XL184
mTOR inhibitors
PI3K inhibitors
BEZ235, XL765
PKC
Enzastaurin
PDGFR inhibitors
Proteasome
Bortezomib
Raf
Sorafenib
Src
Dasatinib
TGF-
AP12009
Combination therapies
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
n e w e ng l a n d j o u r na l
of
m e dic i n e
35905
ISSUE:
7-31-08
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.
References
1. Louis DN, Ohgaki H, Wiestler OD, et
al. The 2007 WHO classification of tumors of the central nervous system. Lyon,
France: IARC Press, 2007.
2. CBTRUS 2008 statistical report: primary brain tumors in the United States,
1998-2002. Central Brain Tumor Registry
of the United States, 2000-2004. (Accessed
July 7, 2008, at http://www.cbtrus.org/
reports/2007-2008/2007report.pdf.)
3. Sathornsumetee S, Rich JN, Reardon
DA. Diagnosis and treatment of highgrade astrocytoma. Neurol Clin 2007;25:
1111-39.
4. Fisher JL, Schwartzbaum JA, Wrensch
M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin 2007;25:867-90.
5. Hardell L, Carlberg M, Soderqvist F,
Mild KH, Morgan LL. Long-term use of
cellular phones and brain tumours: increased risk associated with use for > or =10
years. Occup Environ Med 2007;64:626-32.
6. Lahkola A, Auvinen A, Raitanen J, et
al. Mobile phone use and risk of glioma in
5 North European countries. Int J Cancer
2007;120:1769-75.
7. Inskip PD, Tarone RE, Hatch EE, et al.
Cellular-telephone use and brain tumors.
N Engl J Med 2001;344:79-86.
8. Linos E, Raine T, Alonso A, Michaud
D. Atopy and risk of brain tumors: a metaanalysis. J Natl Cancer Inst 2007;99:154450.
9. Wrensch M, Wiencke JK, Wiemels J, et
al. Serum IgE, tumor epidermal growth
factor receptor expression, and inherited
polymorphisms associated with glioma
survival. Cancer Res 2006;66:4531-41.
10. Farrell CJ, Plotkin SR. Genetic causes
of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and
other syndromes. Neurol Clin 2007;25:
925-46.
11. Malmer B, Adatto P, Armstrong G, et
al. GLIOGENE, an international consortium to understand familial glioma. Cancer Epidemiol Biomarkers Prev 2007;16:
1730-4.
12. Louis DN, Ohgaki H, Wiestler OD, et
al. The 2007 WHO classification of tu-
505
The
n e w e ng l a n d j o u r na l
506
of
m e dic i n e
Medical Progress
78. Westphal M, Ram Z, Riddle V, Hilt D,
507