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Current concepts and management of glioblastoma.

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NEUROLOGICAL PROGRESS
Current Concepts and Management of
Glioblastoma
Matthias Preusser, MD,1 Sandrine de Ribaupierre, MD,2 Adelheid Wöhrer, MD,3
Sara C. Erridge, MD,4 Monika Hegi, PhD,5 Michael Weller, MD,6 and Roger Stupp, MD5,7
Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many
medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and
care improve patients’ life expectancy and quality of life. This review covers major aspects of care of glioblastoma
patients with a focus on the management of common symptoms and complications. We aim to provide a guide for
clinicians confronted with glioblastoma patients in their everyday practice.
ANN NEUROL 2011;70:9–21
G
lioblastoma is the most common malignant primary
brain tumor in adults and among the most aggressive
of all tumors.1 Recent therapeutic advances have led to significant improvements in both patients’ life expectancy and
quality of life. Modern management of glioblastoma requires
a coordinated effort by many disciplines, including neuroradiology, neurosurgery, neuropathology, neurology, radiation,
and medical oncology, as well as rehabilitation and psychological support. Treatment is administered to a great extent
in the outpatient setting, and knowledge of the principles of
care is becoming increasingly important also for office-based
medical specialists and general practitioners. Complications
like thromboembolic events and seizures are frequent and
need to be recognized. Despite the undeniable advances,
most patients ultimately die of their disease; supportive and
end-of-life care close to home are needed. This review covers
major aspects of care of glioblastoma patients with a focus
on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted
with glioblastoma patients in their everyday practice.
Definition and Clinical Presentation
Glioblastoma is a diffusely growing malignant brain neoplasm with characteristic histological features (Fig 1).1 By
definition, glioblastoma corresponds to grade IV astrocytoma, the highest and most aggressive grade. Most cases
of glioblastoma (>90%, primary glioblastoma) develop
rapidly with a clinical history of only a few days or weeks
(de novo). Some glioblastomas (10%) progress gradually
from a lower grade glioma (grade II or III) and are also
referred to as secondary glioblastoma. Although molecularly distinct, primary and secondary glioblastoma are
histologically indistinguishable. Recently, mutations of
the isocitrate (IDH) 1 and IDH2 genes have been identified in >80% of all secondary glioblastoma cases,2 and
with the availability of a monoclonal antibody that specifically recognizes the IDH1 R132H mutation, which
accounts for >90% of all IDH1 mutations in gliomas,
this will soon become routinely detectable by immunohistochemistry.3 The initial clinical presentation is highly
variable and depends primarily on the localization and
size of the tumor. Common symptoms include focal neurological signs (aphasia, paresthesia, hemiparesis, visual
disturbances), mood and personality changes, seizures, or
symptoms of increased intracranial pressure such as nausea, vomiting, or headache. Neurological symptoms
usually prompt imaging, where magnetic resonance imaging (MRI) is now the imaging technique of first choice
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22425
Received Jan 23, 2011, and in revised form Mar 10, 2011. Accepted for publication Mar 11, 2011.
Address correspondence to Dr Stupp, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne,
Rue du Bugnon 46, CH-1011 Lausanne, Switzerland. E-mail: Roger.Stupp@chuv.ch
From the 1Department of Medicine I/Oncology, Comprehensive Cancer Center Central Nervous System Tumors Unit, Medical University of Vienna, Vienna,
Austria; 2Department of Clinical Neurological Sciences, University of Western Ontario, London Health Sciences Centre, London, Ontario, Canada; 3Institute
of Neurology, Comprehensive Cancer Center Central Nervous System Tumors Unit, Medical University of Vienna, Vienna, Austria; 4Edinburgh Cancer
Centre, University of Edinburgh, Edinburgh, United Kingdom; 5Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois and University of
Lausanne, Lausanne, Switzerland; 6Department of Neurology, University Hospital Zurich, Zurich, Switzerland; and 7Department of Oncology/Hematology
Riveria Chablais, Vevey, Switzerland.
C 2011 American Neurological Association
V
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FIGURE 1: Neuropathology of glioblastoma. (A) Histopathology of a typical case of glioblastoma showing cellular glial tumor
tissue with central necrosis (x) with perinecrotic nuclear pseudopalisading and microvascular proliferates (arrows; hematoxylin
& eosin staining; original magnification, 3100). (B) Immunostaining for the astroglial marker glial fibrillary acidic protein shows
strong labeling of the tumor cells (brown signal; original magnification, 3400). (C) Immunostaining for the endothelial marker
CD34 shows glomeruloid microvascular proliferates (original magnification, 3200). (D) Immunostaining for the cell-cycle–
related antigen Ki67 shows that many tumor cells undergo mitosis (brown signal; original magnification, 3400).
(Fig 2). Positron-emission tomography or advanced MRI
modalities (eg, perfusion imaging, diffusion imaging,
magnetic resonance spectroscopy) may be useful in
selected cases, for example, for selection of biopsy targets
or differentiation of recurrent tumor from treatmentrelated changes.
Epidemiology
Glioblastoma accounts for approximately 50% of gliomas
(Fig 3).1 The yearly incidence is 3 to 5 newly diagnosed
cases per 100,000 population.4–6 Glioblastoma incidence
seems to be up to twice as high in European descendants
as compared to African American or Asian descendants.4,5 Although glioblastoma occurs more frequently in
the elderly (median age, 64 years), it may present at any
age, but is rare in children.5–7 In younger patients, sec10
ondary glioblastoma is more frequent (median age, 45
years).8 There is a slight preponderance of glioblastoma
in males, with a male to female ratio of approximately
1.3 to 1.1
Etiology
The etiology of glioblastoma remains largely unknown.
Established risk factors include exposure to ionizing radiation and genetic predisposition.7 There is inconclusive
evidence for an association with occupational risk factors,
exposure to electromagnetic fields, brain trauma, and
nutritional intake of N-nitroso compounds.7 Repeatedly,
concern about an increased risk of glioblastoma due to
the use of mobile phones has been raised. To date, large
population-based studies have found no increase in the
risk of glioma development related to mobile phone use;
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FIGURE 2: Magnetic resonance imaging (MRI) of a typical case of glioblastoma (courtesy of Julia Furtner, MD, Medical University of Vienna). (A) On axial postcontrast T1-weighted MRI, the tumor shows an irregular peripheral ringlike contrast enhancement, with central necrosis in the left thalamic region. The tumor is associated with significant mass effect, with consecutive
compression of the left lateral ventricle and slight midline deviation of the septum pellucidum. (B) Axial T2-weighted MRI
shows a heterogeneous hyperintense mass surrounded by a hyperintense signal extending along the adjacent white matter
indicating tumor extension and edema.
however, the effect of long-term use remains to be evaluated.9,10 In <5% of all glioblastoma cases, other family
members have also been affected with a primary brain
tumor. In most familial cases, the underlying cause is
unknown. The risk for glioblastoma is increased in rare
genetic tumor syndromes, including Li Fraumeni syndrome (TP53 mutations), Turcot syndrome (APC,
MLH1, MSH2, MSH6, PMS2 mutations), and neurofibromatosis 1 (neurofibromin mutations) and 2 (merlin
mutations).1 Recently, several common low-penetrance
susceptibility alleles contributing to the risk of developing
glioma have been reported.11,12
bination of prognostic factors receiving combined radiochemotherapy have 2- and 5-year survival rates of
approximately 40% and 30%, respectively.13,14
Pathobiology and Molecular Biomarkers
Cell of Origin
It remains unclear what initiates the development of glioblastoma and in which cells initial malignant transformation takes place. Several studies in genetically engineered
mice indicate that neural stem or progenitor cells can
give rise to malignant gliomas initiated by mutations frequently found in human glioblastoma, whereas more
Prognosis and Patient Risk Stratification
The overall median progression-free and overall survival
times for patients treated with the current standard chemoradiotherapy within large clinical trials are approximately 7 and 15 months, respectively.13,14 In selected
patient populations within recent clinical phase II trials,
median overall survival of 19 to 22 months has been
shown repeatedly, reflecting in part also improvement in
supportive care and more aggressive salvage therapy.
Patient age, patient mental status, postoperative Karnofsky or World Health Organization performance scores,
which measure the patients’ general condition, and the
extent of neurosurgical tumor resection are important
clinical prognostic factors. Grouping of these factors by
recursive partitioning analysis has identified 3 separate
classes of glioblastoma with distinct prognosis and outcome (Table 1).15 Patients with the most favorable comJuly 2011
FIGURE 3: Relative frequencies of gliomas. World Health
Organization tumor grades are given in parentheses. Population-based data are provided by the Austrian Brain Tumor
Registry.
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TABLE 1: Modified European Organization for Research and Treatment of Cancer RPA Classes15
RPA Class for
Glioblastoma
Definition
Median
Survival Time
2-Year Survival
Rate
5-Year
Survival Rate
III
Age <50 years and WHO PS 0
18.7 months
40.5%
28%
IV
Age <50 years and WHO PS 1 or 2;
or age 50 years, complete or partial
resection, and MMSE 27
16.3 months
29.1%
8.9%
V
Age 50 years, biopsy only,
and MMSE <27
10.7 months
18.2%
3.4%
MMSE ¼ Mini Mental State Examination; PS ¼ performance score; RPA ¼ recursive partitioning analysis; WHO ¼ World
Health Organization.
differentiated cell types seem less susceptible to malignant
transformation.16
Brain Tumor Stem Cells
Cancer stem cells are defined as cells with the ability for
self-renewal, extensive proliferative capacity, and the potential for multilineage differentiation and tumor initiation,
and have been identified in a number of malignancies. In
glioblastoma, cancer stem cells (brain tumor stem cells
[BTSC]), also often referred to as glioma-initiating or glioma-propagating cells, are thought to represent a small subpopulation of cells giving rise to all types of tumor cells
and seem exquisitely resistant to conventional therapeutic
interventions.17,18 The lack of robust markers allowing the
identification of BTSC is an obstacle in the development
of specific treatments. Current studies aim at extending
knowledge of BTSC biology to form a basis for development of BTSC-depleting therapies, which include efforts to
differentiate BTSC in the tumors.19
Aberrant Signaling Pathways and Molecular
Subclassification
Molecular alterations in glioblastoma are associated with
deranged regulation of signaling pathways for cell proliferation, apoptosis, senescence, migration, and cell-to-cell communication. Molecular alterations are complex and diverse
in glioblastoma and have been reviewed extensively elsewhere.1,20 However, distinct molecular pathways show frequent alterations, which seem to be pathobiologically relevant and may be specifically targeted by therapeutic
interventions. Three critical pathways are each affected in
approximately 80% of glioblastomas, and include alterations of receptor tyrosine kinase/Ras/phosphatidylinositol 3kinase, p53, and retinoblastoma signaling.1,20 Recently, a
clinically relevant molecular subclassification of glioblastoma
into proneural, neural, classical, and mesenchymal subtypes
based on genetic aberrations and gene expression of EGFR,
NF1, PDGFR, and IDH1 genes has been proposed.21 Fur12
thermore, a subset of glioblastoma tumors harbor characteristic promoter DNA methylation alterations, referred to as
glioma CpG island methylator phenotype (G-CIMP).22 GCIMP glioblastomas have distinct molecular features
including a high frequency of IDH1 mutation and characteristic copy-number alterations. Glioblastoma patients with
G-CIMP tumors are younger at diagnosis and have
improved survival times.
Hypoxia, Angiogenesis, and Invasion
Hypoxia plays a central role in the pathobiology of glioblastoma. The key mediator—the transcription factor hypoxiainducible factor 1 (HIF-1)—is stabilized under hypoxic
conditions. Although acute hypoxia can induce cell death,
exposure to chronic or repeated hypoxia initiates adaptive
metabolic changes and selects for genetic alterations allowing survival and proliferation in a hypoxic environment.23
Hypoxia-driven physiologic changes include regulation of
the glycolytic pathway, blood-vessel formation, and induction of genes encoding chemotactic molecules such as chemokine ligand 2, interleukin 8, and vascular endothelial
growth factor (VEGF).24 In cancer, such changes are associated with recruitment of macrophages along a hypoxiamediated chemotactic gradient. Recruited macrophages
exert a tumor-promoting effect through the expression of
genes with mitogenic, angiogenic, and migration/invasion
stimulating properties, such as VEGF, EGF, or HGH.25,26
These hypoxia driven changes, affecting also tumor host
interaction, are implicated in resistance of glioblastoma to
chemotherapy and radiotherapy.18 Interestingly, HIF-1 can
also be activated by growth factor receptors and oncogenic
signaling pathways.23
O6-Methylguanine-Methyl-Transferase Gene
Promoter Methylation
O6-Methylguanine-methyl-transferase (MGMT) gene promoter methylation has emerged as a promising molecular
biomarker in glioblastoma.27,28 MGMT is a repair protein
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FIGURE 4: Typical radiotherapy plan for focal irradiation of a glioblastoma. To achieve focused radiotherapy, patients first have a
bespoke immobilization mask made before they undergo a computed tomography scan, usually with intravenous contrast, which
is then fused with the postoperative magnetic resonance imaging scan. The fused images are used to plan the radiotherapy using
multiple high-energy photon beams shaped to minimize the dose to adjacent critical structures (eg, brainstem, chiasm) and to the
rest of the brain to minimize the aftereffects of radiotherapy. (A) Target delineation showing a glioblastoma in the left parietal
lobe with the gross target volume outlined in blue, the clinical target volume covering a 2cm margin of possible microscopic
spread in green, and the planning target volume (PTV) with a 0.5cm margin to account for day to day setup variability in red. (B)
Radiotherapy plan showing the same patient’s plan using 3 fields, with the high dose in orange conforming to the shape of the
PTV. The blue color represents the volume of brain receiving 50% of the prescribed dose.
that removes alkyl groups from the O6 position of guanine
and thus counteracts the effect of alkylating drugs like
nitrosoureas or temozolomide.28,29 MGMT protein expression is repressed by epigenetic methylation of the MGMT
gene promoter. Methylation of the MGMT promoter can
be demonstrated in 30 to 60% of glioblastoma patients
and is associated with favorable outcome in patients treated
with alkylating agents.14,28 Prospective studies aiming at
validating the diagnostic accuracy of MGMT testing and
the prognostic/predictive value of MGMT promoter methylation status are ongoing.
Therapy of Newly Diagnosed Glioblastoma
Neurosurgery
Surgical debulking is the initial therapy of choice for glioblastoma and may lead to rapid improvement of symptoms. However, due to the infiltrative growth pattern, residual tumor cells persist despite macroscopically complete
resection. Localization in eloquent areas (eg, primary motor
cortex) or infiltration of the corpus callosum may allow for
only a partial tumor debulking. In primarily unresectable
disease (approximately 20–30% of patients), only a diagnostic biopsy is performed. State of the art planning of the
neurosurgical procedure involves multimodal imaging
including conventional and functional MRI and diffusion
tensor imaging sequences to visualize functional brain areas
July 2011
and fiber tracts. Fluorescence-guided neurosurgery with 5aminolevulinic acid has been shown to enable more complete tumor resections, translating into improvement in the
6-month progression-free survival rates, but without
increase in overall survival.30 Intraoperative monitoring and
cortical and subcortical stimulation reduce the risk of permanent disability.31
Carmustine Wafers
At surgery, biodegradable wafers impregnated with the
cytotoxic agent carmustine (1,2-bis[2-chloreoethyl]-1nitrosourea) can be implanted in the tumor bed. The
wafers release carmustine locally for approximately 3
weeks, resulting in a very modest survival benefit in 2
randomized clinical trials of patients with newly diagnosed and recurrent malignant gliomas, although no benefit could be shown for the subgroup of patients with
glioblastoma.32,33 Although carmustine wafers are generally considered safe, wound healing may be delayed, and
the risk of edema is increased. Cerebrospinal fluid (CSF)
leakage, intracranial infection, and seizures have also
been reported.34 Alterations in the blood–brain barrier
make the interpretation of MRI unreliable. The value of
carmustine wafers in addition to modern standard chemoradiotherapy has not been explored in randomized
trials.
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FIGURE 5: Illustration of the treatment of adult patients with newly diagnosed glioblastoma aged <70 years and with good performance status. Medical prophylaxis against venous thromboembolism with low molecular weight heparin (LMWH) lasts from 12 to 24
hours after neurosurgery until ambulation. Steroids can often be rapidly tapered after resection. Indication of antiseizure prophylaxis
(AED 5 antiepileptic drugs) should be revisited after surgery. Primary Pneumocystis jirovecii pneumonia (PcP) prophylaxis with pentamidine inhalations or oral trimethoprim/sulfamethoxazole is given during concomitant chemoradiotherapy, or if absolute lymphocyte counts <500/mm3, or CD4 <200/mm3. Temozolomide (TMZ) is administered at a dose of 75mg/m2 daily from the first to the last
day of radiotherapy (RT) (usually 60–90 minutes before radiation or in the morning on days without RT), and at a dose of 150–
200mg/m2 daily 3 5 days (d) during the adjuvant/maintenance phase. A total of 6 cycles of maintenance treatment are established,
some investigators prolong therapy for up to 12 cycles despite the absence of data. Antiemetic prophylaxis with metoclopramide is
suggested; during the first days of each treatment cycle, prophylaxis with a 5-hydroxytryptamine antagonist is recommended.
Radiotherapy and Systemic Antineoplastic
Therapy
Concomitant chemoradiotherapy followed by adjuvant or
maintenance chemotherapy with temozolomide (TMZ/
RT!TMZ) is the current standard of care for patients
with newly diagnosed glioblastoma (Figs 4 and 5). In a
randomized phase III trial on 573 patients, investigators
from the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute
of Canada (NCIC) demonstrated significantly improved
survival with the early addition of temozolomide (TMZ)
to radiotherapy (RT) compared to initial RT alone (Fig
6).13,14 Although median survival was improved from
12.1 to 14.6 months, the 2-year and 5-year survival rates
with RT versus TMZ/RT!TMZ were 11% versus 27%
and 2% versus 11%, respectively. The TMZ/RT!TMZ
regimen is well tolerated, with severe but manageable
hematotoxicity in approximately 7% of patients. The
addition of TMZ during and after RT has had no significant effect on patients’ quality of life.35
FIGURE 6: (A) Kaplan-Meier curve showing that combined radiochemotherapy (RT) with temozolomide (TMZ) is associated with
more favorable patient survival times than RT alone. (B) Kaplan-Meier curves showing the association of O6-methylguaninemethyl-transferase (MGMT) promoter methylation status with patient survival times in relation to type of adjuvant therapy.
MGMT methylation (Meth) is associated with favorable survival, particularly in patients treated with combined RT with TMZ.
Figure adapted from Stupp et al14 with permission from Elsevier, Maryland Heights, MO. O 5 observed number of events; N
5 total sample size.
14
Volume 70, No. 1
1. TMZ/RT with conventional
5-day TMZ (150–200mg/m2)
in the adjuvant phase
1. TMZ/RT
2. TMZ/RT þ cilengitide
(2,000mg IV twice weekly)
1. TMZ/RT
2. TMZ/RT þ bevacizumab
(10mg/kg IV every 2 weeks)
1. TMZ/RT
2. TMZ/RT þ bevacizumab
(10mg/kg IV every 2 weeks)
1. TMZ/RT or RT
2. TMZ/RT or RT þ herpes simplex
virus-thymidine kinase gene therapy
1. Short course radiation
(40Gy/15 fractions for 3 weeks)
þ concomitant TMZ (75mg/m2 daily)
þ adjuvant TMZ (150–200mg/m2,
day 1–5 of 28 days for 12 cycles)
2. Short course radiation
(40Gy/15 fractions for 3 weeks)
GBM, age 18
years, KPS 60%
GBM, age 18–70 years,
MGMT promoter
methylated, ECOG
PS 0–1, RPA class III–V
GBM, age >18
years, KPS >70%
GBM, age >18
years, WHO PS 2
GBM, age 18–70
years, KPS >70%
GBM, age >65
years, ECOG PS 0–2
RTOG 0525/EORTC
26052-22053
(RTOG & EORTC)
EORTC 26071-22072/
CENTRIC (Merck KGaA)
RTOG 0825(RTOG)
BO21990 (Roche/
Genentech)
ASPECT (Ark therapeutics)
NCIC-CE6/EORTC
26062-22061
(NCIC & EORTC)
560
251
MGMT promoter methylation
status included in analysis,
preliminary results reported74
Elderly patients, aged >65 years
920
720
504
(accrual
complete)
1,173
(accrual
complete)
Patients
Required, No.
Bevacizumab starts simultaneously
with chemoradiotherapy
Bevacizumab starts in week
4 of chemoradiotherapy
Only patients with methylated
MGMT promoter eligible
MGMT promoter methylation
status as stratification factor,
dose-dense TMZ in adjuvant phase
Remarks
OS
OS, TTR
OS, PFS
OS, PFS
OS
OS
Primary
Endpoint
2012
2011
2013
2013
2013
2011
Results
Expected
TMZ/RT is standard therapy regimen for newly diagnosed GBM.
ECOG ¼ Eastern Cooperative Oncology Group; EORTC ¼ European Organization for Research and Treatment of Cancer; GBM ¼ glioblastoma; IV ¼ intravenous; KPS ¼ Karnofsky performance score;
MGMT ¼ O6-methylguanine-methyltransferase gene; NCIC ¼ National Cancer Institute of Canada; OS ¼ overall survival; PFS ¼ progression-free survival; PS ¼ performance score; RT ¼ radiotherapy;
RTOG ¼ Radiation Therapy Oncology Group; TMZ ¼ temozolomide; TTR ¼ TTR time to reintervention; WHO ¼ World Health Organization.
2. TMZ/RT with TMZ on
21 of 28 days (100mg/m2)
for 6 cycles in adjuvant phase
Investigational Arms
Selected Eligibility
Criteria
Trial (sponsor)
TABLE 2: Selected Ongoing Phase III Trials in Newly Diagnosed GBM
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Recent trials (Table 2) are focusing on dose-intensification
of TMZ or the addition of novel agents to the EORTCNCIC regimen. The rationale for alternative TMZ schedules and dose-intensification is to overcome chemotherapy
resistance mediated by MGMT. Uncontrolled phase II trials have evaluated the addition of a novel agent to the
standard regimen. Recent examples are the antiglutamatergic 3rd generation anticonvulsant talampanel,36 immunostimulatory therapy with polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose,37 antiVEGF therapy with bevacizumab,38 and the integrin-inhibitor cilengitide,39 all reporting a median survival of 17 to
25 months, improved over the historical control. However,
in the absence of a contemporary randomized control arm,
no conclusions on efficacy can be drawn. Consequently,
the integrin-inhibitor cilengitide, which interferes with cell
adhesion and migration, and the anti-VEGF antibody bevacizumab are being investigated in large randomized phase
III trials (CENTRIC trial/EORTC 26052-22053, RTOG
0825, and Roche/Genentech BO21990; see Table 2).
Elderly Patients
Almost half of the glioblastoma cases occur in patients
>65 years of age, whereas in clinical trials the median
age is usually between 50 to 55 years. In elderly patients,
the reported median survival times are considerably
shorter (4–11 months), and simpler and shorter therapeutic interventions may be warranted.40,41 A small trial
of 85 patients aged >70 years randomized between RT
(25 1.8Gy) versus best supportive care alone demonstrated improved survival with RT (median survival, 6.8
months vs 4.0 months), thus confirming the benefit of
RT also in the elderly population.41 To shorten treatment
duration, hypofractionated RT (fewer RT sessions with
increased fraction doses) is often preferred for elderly
patients; equivalence has been suggested for a hypofractionated radiation schedule (40Gy in 15 fractions over 3
weeks) compared with a standard 6-week schedule (60Gy
in 30 fractions over 6 weeks).40
The value of chemoradiotherapy has not been formally investigated in elderly patients, as the EORTCNCIC trial only included patients up to age 70 years.13
A survival benefit was suggested in all age groups,
although the absolute benefit was larger in younger
patients. Despite the potentially higher toxicity in elderly
patients, standard TMZ/RT!TMZ may be considered
in selected patients with good prognostic factors.42,43
Recently, the results of 2 randomized phase III trials
comparing TMZ alone with RT alone in elderly glioblastoma patients have been reported. Initial results from the
Nordic Glioma Trial suggest a similar outcome of TMZ
16
chemotherapy alone compared to radiotherapy alone,
whereas preliminary data from the German Neuro-Oncology Working Party NOA-08 trial indicate that doseintensified TMZ alone may be inferior to RT alone in
the primary treatment of older patients (aged >60 years
in the Nordic trial, 65 years in the NOA trial) with
malignant glioma.44,45 An ongoing NCIC-EORTC Intergroup trial compares hypofractionated RT with or without concomitant and maintenance TMZ in glioblastoma
patients aged >65 years (see Table 2).
Therapy for Recurrent Glioblastoma
Despite the advances in therapy for newly diagnosed
glioblastoma, virtually all patients will experience tumor
recurrence. Since the introduction of TMZ chemotherapy in first-line treatment together with RT, no single
treatment can be considered standard of care, and proposed therapies vary greatly. Available evidence stems
largely from uncontrolled phase II trials or large retrospective series. Selected patients may benefit from repeat
surgery (with or without implantation of carmustine
wafers), and focused reirradiation with conventional or
stereotactic radiotherapy is also increasingly being considered. For most patients, chemotherapy remains the treatment of choice at recurrence, although for patients with
a substantially reduced performance status, supportive
care measures alone may be more appropriate.
For patients with a treatment-free interval of several
months since the end of initial TMZ chemotherapy, re-exposure to TMZ may be considered. Alternative schedules
of TMZ administration with a so-called dose-dense or
metronomic regimen have been advocated; however, the
evidence remains circumstantial and inconclusive.46–48
Modulation of MGMT-associated chemoresistance by the
addition of MGMT inhibitors like O6-benzylguanine to alkylating chemotherapy is being evaluated in clinical trials.49
In a randomized British trial, 447 chemonaive patients
with recurrent glioma were randomized to either PCV
chemotherapy (procarbazine, lomustine [CCNU], vincristine) or TMZ, with a second randomization of either a 5day or a 21-day TMZ regimen.50 This trial demonstrated
equivalence of PCV and TMZ, but in patients receiving
TMZ the standard 5-day schedule had superior overall
progression-free survival and short-term quality of life as
compared to the dose-dense 21-day administration. The
reasons behind this are uncertain, but it may be that the
maximal drug level is more important than duration of
exposure and total dose. Similarly, nitrosoureas (CCNU,
carmustine), platinum-based chemotherapy, or irinotecan
(CPT11) are valid options. Lomustine has consistently
shown clinical activity in several recent randomized trials
where this agent was evaluated as the control arm.51
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Targeted strategies of inhibition of VEGF-mediated
signaling have received considerable attention recently. Bevacizumab, a neutralizing monoclonal antibody against
VEGF, has demonstrated high radiographic response rates,
a decreased need for corticosteroids, and temporary
improvement in neurological function in several uncontrolled studies.38,52 In a pivotal trial overall survival was
9.2 months (95% confidence interval, 8.2–10.7), with
42.6% (confidence interval, 29.6–55.5%) of patients alive
and progression-free at 6 months.38 The US Food and
Drug Administration provisionally approved bevacizumab
for use in recurrent glioblastoma, whereas the European
Medicines Agency rejected the application. The main concerns of the European committee were that the conventional response criteria may not be appropriate for evaluation of efficacy, with overestimation of bevacizumabinduced tumor shrinkage due to modification of the
blood–brain barrier without antitumor effect and the absence of a control arm in all studies. The increase in median overall survival of <2 to 3 months compared to historical controls was considered insufficient in the absence
of a randomized comparator. The effect of bevacizumab is
most pronounced in patients with significant peritumoral
edema, and the responses observed may be largely due to
its corticosteroidlike effect on the blood–brain barrier.
Optimal dose and frequency are not yet established. It has
been indicated that bevacizumab treatment may increase
the rate of distant and diffuse tumor progression by
increasing the tendency of tumor cells to invade the brain
parenchyma along pre-existing vasculature (vascular cooption).53 However, this observation could not be confirmed in other studies.54–56 Similarly, promising initial
results have been observed with the VEGF receptor tyrosine kinase inhibitor cediranib.57 However, a well-designed
controlled randomized phase III trial (REGAL study) failed
to demonstrate improved survival with cediranib alone
(median overall survival, 8.0 months; hazard ratio, 1.43;
95% confidence interval, 0.96–2.13) or in combination
with CCNU (median overall survival, 9.4 months; hazard
ratio, 1.14; 95% confidence interval, 0.76–1.71) compared
to standard chemotherapy (CCNU) alone (median overall
survival, 9.8 months),58 although progression-free survival
rate at 6 months, response rate, and time to neurological
deterioration were improved in the combination arm. In
accordance with previous observations, the normalization
of vascular permeability led to a substantial reduction of
corticosteroid requirements.
Novel Approaches
A large number of targeted agents and novel approaches
are being developed and evaluated in malignant glioma;
July 2011
a comprehensive review on this topic is beyond the scope
of this article, but has been provided elsewhere.59,60
Unfortunately, to date clinical trials with single-agent targeted therapies including erlotinib, gefitinib, imatinib,
temsirolimus, everolimus, and enzastaurin have largely
been disappointing.51,61–67 A reason for this could be
that glioma cells rely on multiple redundant pathways.
Therefore, current trials are trying to overcome tumor
cell resistance by combining targeted agents or by combining them with RT or cytotoxic chemotherapy. Vaccination strategies using autologous dendritic cells pulsed
with tumor lysate antigen or targeting the EGFR variant
III, which is a tumor-specific epitope not expressed in
any normal adult human tissue, have shown some promise and are being evaluated in clinical trials, although a
randomized trial was closed early due to insufficient
patient accrual.68,69 Another novel approach is intraoperative injection of herpes simplex virus-thymidine kinase
gene vectors (Cerepro) into the tumor bed, followed by
several days of intravenous ganciclovir infusions.70 Radioimmunotherapy with radiolabeled monoclonal antibodies
against tumor-relevant antigens like epidermal growth
factor receptor (EGFR), tenascin, and integrins has
shown promising efficacy against malignant glioma in
some preclinical and early clinical studies.71,72 A novel
treatment modality using alternating electrical currents
(NovoTTF) has been investigated in a randomized trial
comparing it to the best available chemotherapy in recurrent glioblastoma. Preliminary results suggest that this
approach produces results similar to those of chemotherapy, and objective responses have been observed in 12%
of patients.73 A randomized phase III trial in newly diagnosed patients in combination with temozolomide is
ongoing.
Management of Common Symptoms and
Complications
Seizures
Up to 30 to 40% of malignant glioma patients have seizures at presentation or experience seizures during their
disease course.74–76 General guidelines for therapy of epilepsy apply, whereas prophylactic antiepileptic drug
(AED) therapy in patients without a history of seizures is
not recommended.77–80 Antiepileptic monotherapy is
associated with higher compliance and less adverse
effects.81 Special consideration should be given to the
choice of AED and potential interaction with current or
future chemotherapy agents.80 Older AEDs induce hepatic cytochrome P450-mediated metabolism and thus
substantially increase the metabolism of most antineoplastic drugs (except nitrosoureas and temozolomide)
17
ANNALS
of Neurology
TABLE 3: Overview of Antiepileptic Drugs Commonly Used in Glioblastoma Patients
EIAED/Non-EIAED
Drug
Common Adverse Effects
EIAED
Phenobarbital
Sedation, rash, impaired cognitive function
Phenytoin
Gingival hypertrophy, hirsutism, hepatotoxicity,
rash, lymphadenopathy
Carbamazepine
Drowsiness, dizziness, diplopia, rash, leukopenia,
hyponatremia, hepatotoxicity, nausea/vomiting, cardiac arrhythmia
Oxacarbazepine
Drowsiness, dizziness, diplopia, rash, hyponatremia,
hepatotoxicity, nausea/vomiting
Valproic acid
Weight gain, nausea/vomiting, hair loss,
thrombocytopenia, hepatotoxicity
Gabapentin
Somnolence, dizziness, agitation/anxiety, ataxia
Lamotrigine
Somnolence, dizziness, rash, hepatotoxicity
Levetiracetam
Drowsiness, fatigue, agitation/anxiety, headache
Pregabalin
Somnolence, dizziness, weight gain, ataxia
Non-EIAED
EIAED ¼ enzyme-inducing antiepileptic drug.
(Table 3). Hence, non–enzyme-inducing AEDs are now
increasingly used. Of note, almost 25% of brain tumor
patients experience adverse effects from AEDs severe
enough to necessitate a change or discontinuation of
antiepileptic therapy (see Table 3).
Brain Edema
Brain edema in gliomas is primarily the result of leakage
of plasma into the tissue through dysfunctional cerebral
capillaries (vasogenic edema) and is detectable on T2weighted or fast fluid-attenuated inversion recovery magnetic resonance images.82 Brain edema is associated with
increased intracranial pressure with headache, vertigo,
and nausea/vomiting and can lead to life-threatening
brainstem compression and herniation. Dexamethasone is
usually the drug of choice. This long-acting corticosteroid can be administered orally or intravenously at equal
efficacy. Initial doses are typically 12 to 16mg per day;
doses >16mg per day have not been shown to increase
efficacy. Steroid dosage should be rapidly reduced and
tapered to individual needs; a recent review advocates the
use of medium doses (4–8mg) in most patients without
midline shift.83,84 In emergency situations, intravenous
dexamethasone may be combined with osmotic agents
such as mannitol or glycerol.82,84 If there is obstructive
hydrocephalus secondary to the tumor diversion of the
CSF, using a shunt may be required to palliate the symptoms of raised intracranial pressure.
Venous Thromboembolism
Up to 30% of malignant glioma patients develop deep
venous thromboembolism (DVTE) at some point in the
18
course of their disease.85–89 The exact mechanism leading
to hypercoagulability in malignant glioma patients is
unclear; however, there is evidence that tissue factor,
which is a major initiator of the extrinsic coagulation cascade expressed in gliomas, may be pathogenetically relevant. Other risk factors include neurological deficits associated with reduced mobility, large and incompletely
resected tumors, frontal tumor location, age >60 years,
and the use of corticosteroids.85,86,89
Due to the inherent bleeding risk, anticoagulation
has long been considered contraindicated for brain tumor
patients. Recent studies demonstrate that prophylactic low
molecular weight heparin (LMWH) administration in the
immediate postoperative phase effectively reduces DVTE
risk, while only slightly increasing the risk of hemorrhage.87,90 Compression stockings beginning 12 to 24
hours after neurosurgery together with prophylactic
LMWH are recommended until ambulation unless there is
pre-existing increased bleeding risk (bleeding diathesis). No
data are available for prolonged thrombosis prophylaxis.
One randomized phase III trial (PRODIGE study) investigating dalteparin LMWH for long-term prophylaxis of
DVTE was discontinued prematurely after recruitment of
186 of the planned 512 patients due to withdrawal of
drug supply by the manufacturer.88 The available results
indicate a trend toward reduction of thrombotic events
with only a slightly increased risk of intracranial hemorrhage in patients receiving dalteparin. In case of established
DVTE, treatment and secondary prophylaxis is usually
done with LMWH (enoxaparin or dalteparin). There are
no randomized trials comparing LMWH to other strategies
such as warfarin, acetylsalicylic acid, or cava filters. Recent
Volume 70, No. 1
Preusser et al: Glioblastoma
data indicate that laboratory blood parameters such as Ddimer and prothrombin fragments 1 and 2 may be useful
for assessment of patient risk for DVTE and may help to
individualize thromboprophylaxis.91 Future studies may
define the role of emerging oral factor Xa (eg, rivaroxaban)
and thrombin inhibitors (eg, dabigatran etexilate) in glioblastoma patients.
Merck-Serono. M.W.: grants/grants pending, Roche, Merck
Serono; honoraria, Roche, Merck Serono, MSD; patents,
Merck Serono. R.S.: grants/grants pending, Merck KGaA,
Novocure Ltd; honoraria (advisory board), Merck KGaA,
Darmstadt, Roche, MSD/Essex Chemie, OncoMethylome
Sciences; travel expenses, Merck KGaA, Darmstadt.
End of Life Care
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care services is important to ensure that the needs of the
patients and their caregivers are met. However, there is
lack of data to guide psychosocial and supportive care.92
The most frequent symptoms in the last month of life
are seizures, headache, drowsiness, dysphagia, and eventually death rattle, agitation, and delirium. The most commonly used drugs in this phase are AEDs, corticosteroids, and analgesics, including opioids and
sedatives.93,94 Owing to unconsciousness or difficulties in
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individually, as the benefits and burdens are unclear, and
no evidence-based guidelines exist.95 If possible, end-oflife preferences should be discussed with patients and
their families early in the disease course. The interface
between community healthcare services and specialists is
essential to ensure that patients receive optimal palliative
care, avoiding useless emergency rehospitalization in the
terminal phase. Recently, the successful implementation
of a multidisciplinary home care palliative unit for brain
tumor patients in Italy has been reported and represents
an alternative to in-patient care.94 In this study, 82% of
patients experienced a peaceful death at home with good
symptom control and without pharmacological sedation.
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Potential Conflicts of Interest
M.P.: grants/grants pending, travel expenses, Roche. M.H.:
consultancy, MDxHealth (Oncomethylome Sciences),
Merck-Serono; grants/grants pending, AstraZeneca, MerckSerono, Oncomethylome Sciences; speaking fees, MerckSerono, MSD; travel expenses, Oncomethylome Sciences,
July 2011
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