Glioblastoma Multiforme: A Review of Where We Have Been and Where We Are Going

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Glioblastoma multiforme: A review of where we have been and where we are

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Article in Expert Opinion on Investigational Drugs · June 2009

DOI: 10.1517/13543780903052764 · Source: PubMed
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Review
Glioblastoma multiforme:
a review of where we have
been and where we are going
1. Overview of glioblastoma Cory Adamson†, Okezie O Kanu, Ankit I Mehta, Chunhui Di, Ningjing Lin,
2. Glioblastoma pathology Austin K Mattox & Darell D Bigner
and molecular biology †Duke Medical Center, Durham, North Carolina, USA
3. Glioblastoma immunology
Malignant gliomas such as glioblastoma multiforme (GBM) present some of
4. ‘Where we have been’
the greatest challenges in the management of cancer patients worldwide,
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Yeshiva University on 10/17/13
5. ‘Where we are now’ despite notable recent achievements in oncology. Even with aggressive surgical
6. ‘Where we are going’ resections using state-of-the-art preoperative and intraoperative neuroimaging,
7. Conclusion along with recent advances in radiotherapy and chemotherapy, the prognosis
for GBM patients remains dismal: median survival after diagnosis is about
8. Expert opinion
14 months. Established good prognostic factors are limited, but include young
age, high Karnofsky Performance Status (KPS), high mini-mental status
examination score, O6-methylguanine methyltransferase promoter methylation,
and resection of > 98% of the tumor. Standard treatment includes resection,
followed by concurrent chemotherapy and radiotherapy. GBM research is
being conducted worldwide at a remarkable pace, with some of the more
recent promising studies focused on identification of aberrant genetic events
For personal use only.
and signaling pathways, tumor stem cell identification and characterization,

modulation of tumor immunological responses, combination therapies, and
understanding of the rare long-term survivors. Past treatment strategies have
failed for various reasons; however, newer strategies in trials today and on
the horizon encourage optimism. To help illustrate ‘where we have been’
with this fatal disease and ‘where we are going’ with contemporary studies,
we include in this review a detailed history of Phase III clinical trials for
GBM, with a final emphasis on exciting new treatment strategies that offer
hope for future GBM therapy.
Keywords: GBM, genetics, glioblastoma multiforme, oncogenomics, signaling cascades
Expert Opin. Investig. Drugs (2009) 18(8):1061-1083
1. Overview of glioblastoma
Glioblastoma (GBM) is the most common primary CNS tumor in the USA and
European countries, with about 3 in 100,000 people newly diagnosed with GBM
each year, accounting for > 51% of all gliomas (Figure 1) [1]. Gliomas are categorized
as World Health Organization (WHO) grades I – IV, based on histological char-
acteristics, which carries prognostic and survival correlates. Glioblastoma is a WHO
grade IV glioma, the most malignant grade. For decades, it has been known that
some gliomas of lower WHO grade can recur, progress, or transform into GBM.
These have been termed secondary GBMs, whereas de novo GBM tumors are
termed primary GBMs. The genetic heterogeneity of GBMs underscores the existence
of these two subtypes. For example, recent genome-wide studies have identified
mutations in NADP+-dependent isocitrate dehydrogenase genes that appear frequently
in secondary GBM [2,3].
The mean age of primary GBM patients is about 62, whereas the mean age of
secondary GBM is about 45 [4,5]. The age distribution of GBM varies more with
10.1517/13543780903052764 © 2009 Informa UK Ltd ISSN 1354-3784 1061

All rights reserved: reproduction in whole or in part not permitted
Glioblastoma multiforme: a review of where we have been and where we are going
All other astrocytomas,

8.7% All other gliomas, 11.1%
Ependymomas, 5.8%
Oligodendrogliomas, 8.4%
Pilocytic astrocytoma
(WHO I), 5.8%
Diffuse astrocytoma
(WHO II), 1.5%
GBM (WHO IV), 51.2%
Anaplastic astrocytoma
(WHO III), 7.5%
Figure 1. Distribution of all primary CNS gliomas (n = 26,630). Astrocytomas account for 75% of all gliomas. Astrocytomas arise
specifically from astrocytes, whereas gliomas refer to primary CNS tumors that arise from astrocytes, oligodendrogliomas, or ependymal cells.
Figure adapted from more recent Central Brain Tumor Registry of the United States [1].
the secondary type. Primary GBM develops more frequently probably nonexistent today, since cellphone technology has
in males than in females (M:F ratio = 3:1), whereas the significantly changed over the past decade [24]. Caucasians
reverse is the case for secondary GBM [4,6-11]. Primary GBM are more frequently affected than their Asian or African
is rarely seen in younger patients, constituting only 8.8% of counterparts [5,25-27]. About 5% of gliomas represent familial
all childhood CNS tumors [12]. aggregations, with some seen in known syndromes such as
Population-based studies report that the overall survival of Cowden’s disease, Li–Fraumeni syndrome, and neurofibro-
patients with newly diagnosed GBM is 17 – 30% at 1 year, matosis [18]. Isolated studies have noted some molecular cor-
and only 3 – 5% at 2 years, despite access to state-of-the-art relations with longer survival, such as O6-methylguanine-DNA
modalities of therapy [4,13,14]. Recent meta-analyses of clinical methyltransferase (MGMT) hypermethylation; however, no
trials show that 2-year survival rates can reach 13 – 26%, molecular event has become routinely accepted as a prog-
emphasizing that patients fare better in clinical trials, probably nostic factor, although patients with IDH1 and IDH2
due to improved healthcare, access to therapies, and selection mutations have a much better prognosis [28]. Many analyses
bias [15]. Survival rates do not differ between men and women, have shown that no significant difference exists among clini-
but they are clearly higher for younger patients. Five-year cal and molecular factors, except for IDH1 and IDH1
survival rates are about 13% for patients aged 15 – 45 years, mutations, for longer survival of patients with primary or
and only 1% for those aged ≥ 75 years [13]. secondary GBM, except possibly younger age and a good
The etiology of GBM is unknown. While the incidence initial Karnofsky Performance Status (KPS) [4,5,28]. Age and
of gliomas has been reported by some to be on the rise [16,17], KPS provide the primary prognostic factors in the com-
the predisposing factors are poorly understood [18-21]. The monly used recursive partitioning analyses seen in the Radi-
only proven environmental risk factor for gliomas is expo- ation Therapy Oncology Group and European Organization
sure to ionizing radiation, such as children irradiated for for Research and Treatment of Cancer prognostic classes
leukemia [22]. Many other factors have been suggested, such (Table 1) [29,30].
as exposure to chemical carcinogens in occupations such as The most common presenting symptoms and signs for
rubber manufacturing, petroleum production, vinyl chlo- patients with GBM are progressive focal neurologic deficits,
ride, pesticides, forestry work, and cleaning services, as well headaches, and seizures. Even though the reported incidence
as passive smoking exposure, although none of these are of many asymptomatic benign CNS tumors is increasing
established causes [19]. Interestingly, increasing socioeco- due to the increasing prevalence of neuroimaging, the aggres-
nomic status increases risk for gliomas [23]. A slight increase sive growth of GBMs usually precludes incidental discovery
risk of ipsilateral gliomas was seen in one meta-analysis of these. Diagnosis typically begins with suspicious findings
studying cellphone use for >10 years; however, this risk is on MRI, including T1-weighted images with and without
1062 Expert Opin. Investig. Drugs (2009) 18(8)

Adamson, Kanu, Mehta, Di, Lin, Mattox & Bigner
Table 1. Prognostic classes most commonly used, as 2. Glioblastoma pathology and molecular
proposed by RTOG and EORTC. biology
Class Prognostic factor Median survival Based on a histopathologic diagnosis, GBM consists of poorly
(months) differentiated neoplastic astrocytes, cellular and nuclear atypia,
RTOG brisk mitotic activity, diminished apoptosis, neoangiogenesis,
vascular thrombosis, and pseudopallisading necrosis [31-33].
III Age < 50, KPS 90 – 100 17.9
Vascular hyperproliferation and necrosis are essential diagnostic
IV Age < 50, KPS < 90 features that set GBM apart from lower-grade gliomas. Despite
Age > 50, resection, no neurologic 11.1 its highly invasive and proangiogenic properties, GBM, like
deficits most other malignant CNS tumors, does not metastasize
V Age > 50, KPS 70 – 100, resection outside the CNS.
with neurologic deficits or only Despite a common clinical presentation and histology,
biopsy with > 54.4 Gy GBM has clearly been demonstrated to be a genetically
Age > 50, KPS < 70, no neurologic 8.9 heterogeneous tumor. Current understanding of the molecular
deficits characteristics of this disease has demonstrated that there are
VI Age > 50, KPS 70 – 100, biopsy unlikely to be single genetic or cellular events that can be
only with < 54.4 Gy effectively targeted for all patients. Instead, future therapies
Age > 50, KPS < 70, neurologic 4.6 may require some individualization for each patient’s tumor
deficits genotype or proteomic profile. The birth of this century
EORTC witnessed a new era of investigational drugs, transitioning
III Age < 50, WHO PS 0 17 from the traditional nonspecific chemotherapies of the past
to target-specific, often molecular-based, drugs developed in
IV Age < 50, WHO PS 1 – 2
response to our new understanding of the molecular biology
Age ≥ 50, GTR, MMSE ≥ 27
15 of this deadly tumor.

V Age ≥ 50, biopsy only, MMSE < 27 10 Recent comprehensive genetic screens of GBM have
confirmed that genetic alterations are scattered across the
Note: Age and KPS are the most uniformly used prognostic factors, followed by
entire genome, affecting numerous chromosomes [3,34]. Par-
extent of surgical resection and completion of adjuvant therapies.
EORTC: European Organization for Research and Treatment of Cancer; GTR: Gross ticularly common regions of loss include areas on 1p, 6q,
total resection; KPS: Karnofsky performance status; MMSE: Mini-mental status 9p, 10p, 10q, 13q, 14q, 15q, 17p, 18q, 19q, 22q, and Y [35-40].
examination; PS: Performance Status; RTOG: Radiation Therapy Oncology Many of these genetic losses represent loss of specific tumor
Group; WHO: World Health Organization. suppressor genes with direct effects on gliomagenesis; how-
ever, some of these losses probably represent the inherent
genomic instability that develops in tumor cells. Loss of
gadolinium and T2-weighted images. If patients are unable heterozygosity (LOH) on chromosome 10 is the most fre-
to undergo MRI, a contrast-enhanced CT scan may be quent genetic alteration in GBM, occurring in 60 – 80% of
useful; however, this modality remains far inferior in image cases [41]. Gains of gene expression due to genetic alterations
detail. Glioblastoma is classically hypointense to isointense, at the genomic level have been demonstrated in GBM in
with a ring-pattern of enhancement on gadolinium- the form of duplication of entire chromosomes, intrachro-
enhanced T1 images, and is hyperintense on both T2 and mosomal amplification of specific alleles, extrachromosomal
FLAIR images. It can be focal, multifocal, or diffuse (gliom- amplification (often in the form of double minutes [dmins]),
atosis cerebri). The majority of GBM tumors are found in and activating mutations [40,42,43]. These forms of increased
the frontal lobes of the supratentorial compartments, but gene expression (oncogenic) occur much less frequently than
they also occur in all cortical areas, the cerebellum, brain- losses of gene expression. Clearly, the most common oncogenic
stem, and spinal cord. The vast majority of neoplastic cells event is amplification of the EGFR gene on chromosome 7,
are found within the tumor bed and within 2 cm of the often in the form of dmins [25,44].
enhancing borders; however, migrating cells can be found Gliomagenesis also involves errors in DNA replication,
several centimeters away from the tumor and even in the DNA repair, chromosomal segregation, and alteration of
contralateral hemisphere. Magnetic resonance spectroscopy numerous signaling cascades not directly attributed to
(MRS), MR perfusion, and F18-fluorodeoxyglucose- genomic mutations. This collection of genetic and cellular
positron emission tomography (FDG-PET) are more alterations gives rise to the ‘mutator phenotype’ in glioma
sophisticated imaging tools that can help delineate varied cells [45]. Central to this mutator phenotype are DNA repair
metabolic rates and therapeutic responses. They can be par- mechanisms. There are at least four DNA repair pathways
ticularly useful for differentiating tumor recurrence from that may go awry in GBMs, including nucleotide excision
benign radiation necrosis. repair, base excision repair, mismatch repair, and direct
Expert Opin. Investig. Drugs (2009) 18(8) 1063

reversal of lesions in recombination [45,46]. As one well-studied cell death. Mutations of TP53 occur in some familiar tumor
example, elevated levels of the DNA repair enzyme MGMT syndromes with established associations with malignant
have been demonstrated in GBM [47]. MGMT specifically gliomas (e.g., in Li–Fraumeni syndrome), which underscores
removes promutagenic alkyl groups from the O6-position of its relevance in the pathogenesis of malignant gliomas [64].
guanine in DNA. Therefore, MGMT protects cells against RB1 controls the transition from G1 into S-phase of the cell
carcinogenesis induced by alkylating agents. Repair of cycle by inhibiting the action of elongation factor E2F1,
O6-alkylguanine adducts by tumor cells has been implicated and its expression is commonly altered in GBM. The
in drug resistance, since it reduces the cytotoxicity of alkylating cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phos-
chemotherapeutic agents [48]. Loss of MGMT expression phorylates the RB1 protein, thereby increasing release of the
may be caused by methylation of promoter CpG islands, E2F1 transcription factor that activates genes involved in
which has been observed in gliomas [49,50]. the G1-to-S transition [65].
Despite the development of a mutator phenotype and the Mutations of phosphatase tensin homolog (PTEN) on
plethora of cellular genetic alterations it probably entails, chromosome 10q23, also called MMAC1 and TEP1, occur
there are a number of discrete genetic events and signaling frequently in familial cancer syndromes, such as Cowden’s
pathways that appear to be central to the initiation and pro- syndrome and Bannayan–Riley–Ruvalcaba syndrome, which
gression of GBM (Figure 2) [34]. In GBM, aberrant EGFR and include GBM as part of the clinical spectrum [66,67]. PTEN
other tyrosine kinase receptor autocrine signaling pathways contains a central catalytic phosphatase core domain that
may be the most often-cited pathways. These lead to robust negatively regulates phosphatidylinositol-3 kinase (PI3K) by
alterations in cellular development, proliferation, migration, dephosphorylating phosphatidylinositol-3,4,5 triphosphate (PIP3)
and vacularization. EGFR overexpression is also more common and phosphatidylinositol-3,4 diphosphate (PIP2) [68]. In the case
in primary (40 – 60%) than in secondary (< 10%) GBMs [9]. of mutant PTEN, the elevated lipid second messenger PIP3 is
Amplification of the EGFR gene is often associated with used by PI3K to hyperphosphorylate protein kinase B (PKB)/
structural alterations in the gene. Seven major mutated vari- Akt [69]. This modulates the activity of proteins that play a
ants of EGFR have been identified, the most common being critical role in cell survival, invasion, and proliferation [70].
variant III (EGFRvIII), which is present in 20 – 50% of

GBMs with EGFR amplification [51-54]. In addition to enhancing 3. Glioblastoma immunology
growth, proliferation, migration, and tumor neovascularization,
this truncated receptor also confers resistance to chemo- The relatively recent realization that a robust immune reaction
therapies such as cisplatin through modulation of Bcl-XL can be elicited in the CNS has provided another excited
and caspases in cell death pathways [55]. Platelet-derived source of investigational drugs for treating GBM (see
growth factor receptor (PDGFR) is a similar receptor ‘Immunotherapies’, Table 3). Glioblastoma also alters the
expressed in most types of gliomas [56], whereas EGFR is immunologic profile of the normal CNS environment, pro-
expressed mainly in GBM [57]. PDGFR signals through viding additional opportunities for exploring immune-based
PI3K and PLC-γ [58]. therapies [69]. Glioma cells express numerous tumor-associated
In GBM, specific mutations affecting Ras are very rare; antigens [71,72] that mostly exhibit immunosuppressive activ-
however, high levels of Ras guanosine triphosphate (GTP) ities, such as hindering cell-mediated immunity. Other signs
have been documented in cell lines and primary tumors, of an altered immune system seen in GBM include cutane-
suggesting that this signaling pathway is activated by ous anergy, lymphopenia, impaired antibody production,
upstream factors such as receptor tyrosine kinase activation [59]. reduced lymphocyte protein synthesis, and diminished lym-
Another major way of activating this pathway is via the loss phocyte responsiveness [73-84]. Many complex interactions
of neurofibromin function, the protein product of the large between glioma cells and immune cells are thought to be
neurofibromatosis 1 (NF1) gene. Ras-GTP is downstream of mediated by glioma-derived cytokines such as IL-6, IL-8,
growth factor receptors at a major signal transduction crossroad, TGF-β2, and VEGF. Additionally, glioma cells are thought
translating extrinsic messages into the Raf-MAPKK-ERK, or to induce expression of immunosuppressive factors from
into either the PI3K-PKB or the PI3K-Rac-Rho pathways. other cells within the environment, such as IL-10 and pros-
These influence cell survival and migration. taglandins from monocytes [85]. Some of these factors over-
The majority of malignant brain tumors, including GBM, expressed in GBM have multiple effects. VEGF, which plays
demonstrate inactivating mutations in the TP53 pathway, a key role in tumor neoangiogenesis, also inhibits the matu-
the retinoblastoma (RB1) pathway, or both [60-63]. These ration of dendritic cells from progenitor cells originating
two pathways affect numerous cellular functions and inter- from the bone marrow and promotes GBM tumor cell pro-
act with each other. The TP53 transcription factor is liferation. Exploiting the immune system for investigational
short-lived and is upregulated in response to cellular stress agents may go a long way to enhancing the patient’s own
such as radiation exposure, DNA strand breaks, and toxins. immunotherapy against malignant gliomas and directly killing
It facilitates DNA repair by halting the cell cycle for repair glioma cells. Indeed, several clinical trials are now in progress
enzymes to work; or if the damage is too great, it induces testing immune modulating and therapies (see section 6).


MMP inhibitor EGF
Dendritic XXXXXXXXXX EGFR antibody
(Prinomastat) MMP X cellular matrix XXXX (MDX447)
cell
XXXXXXXXXX
EGFRvIII
Peptide PIP3 PIP2
=
Plasma RAS inhibitor
EGFR
PI3K PTEN
EGFR
membrane PDK2 (TLN-4601) Grb2
SOS Src
AKT
EGFRvIII RAS:GTP RAS:GDP
PIK3 inhibitor Src
TSC2 AKT inhibitor (BEZ235) RAF
EGFRvIII inhibitor
=
(Perifosine) Raf inhibitor
(dasatinib)
TSC1 (TLN-4601)
EGF RTK
RHEB MAPKK inhibitor
mTOR inhibitor
FTI (Erlotinib)
mTOR (Everolimus) VEGFR
inhibitor ERK VEGF
(Tipifarnib) FT Proteosome VEGFR
4EBP1 inhibitor
TF
eIF4E (Bortezomib)
G207 Ad5
(HSVI) CMV-
TGFβ HDAC inhibitor p53 VEGF antibody
inhibitor (Vorinostat) (BevacizumabA)
(AP12009) Sp1 inhibitor
(Terameprocol)
HDAC PARP PARP inhibitor Microtubule
SMAD4 (BSI-201) inhibitor
(CYT997)
TGF
Expert Opin. Investig. Drugs (2009) 18(8)

Type1
II TOPO MGMT
Type2 nucleus
Topoisomerase
TGF inhibitor
antibody (RTA744) MGMT inhibitor
(TP-38) (06-benzylguanine)
IL13R
Avβ5 integrin
Tenascin
Anti-αvβ5 antibody Anti IL13 antibody Anti-Tenascin antibody131I-81c6

(Cilengitide) (IL13-PE38QQR)
Figure 2. Cellular targets for current investigational agents in GBM. Investigational agents are italicized. Target proteins are in gray circles or boxes. Black dots are phosphate groups.
1065
4. ‘Where we have been’ open ventricular system, or an inability to obtain CSF-tight
dural surgical closure. Despite the benefit proven in RCTs,
Clinical research in GBM has a long and prolific history, this therapy never gained universal acceptance, probably due
with reports of hundreds of various types of clinical trials to unfamiliarity with indications for its use, concern for
being published. Indeed, the number of clinical reports of local side effects, and cost. It still remains an important
treatment modalities that has been tested makes summarization option. Despite the numerous studies with BCNU spanning
and interpretation almost impossible. However, one can over four decades, a single study by Stupp and colleageues in
make significant observations by examining the history of 2005 [99] established a new systemic chemotherapy as the
the gold standard clinical trial design in GBM, namely standard of care. Temozolomide, given concomitantly with
Phase III randomized, controlled trials (RCTs) (Table 2). postoperative RT and followed by continued use for 6 –
Numerous early RCTs, even back to the 1960s, were well 12 months after RT, is an orally available therapy with effi-
designed with appropriate randomization schemes and control cacy similar to that of BCNU and less toxicity.
arms, providing sound, evidence-based guidelines. Although One area of extensive investigation is with long-term
its mechanism was not clearly understood, radiation therapy survivors who survive more than 2 – 3 years with GBM.
(RT) was the first postsurgical adjuvant therapy that consis- Some argue that a major contributor to the extended sur-
tently demonstrated efficacy over the 1960s and early 1970s, vival for this very small group of patients may be that those
typically doubling survival from 4 – 6 to 10 – 11 months. patients are involved in clinical trials at academic medical
Whole-brain RT quickly became the standard of care and centers: overall outcomes for these patients are improved
characterized the control arm for future studies. As with simply by their involvement in clinical trials. Therefore, all
other cancers, the nonspecific targeting of rapidly dividing physicians treating GBM patients should be aware of oppor-
cells by RT proved efficacious for GBM. However, some neural tunities for referring their patients to these centers. Even if
structures (e.g., the optic apparatus) are quite sensitive to RT, therapies are not proven to be efficacious in clinical trials,
limiting the total amount of RT that can be tolerated. RT is patients clearly benefit from the increased surveillance of tumor
restricted to individuals aged > 3 years due to the sensitivity recurrence, the vigilant search for therapy toxicities, and
of the newborn brain to RT. Because of the clear benefit of easier access to services such as counseling and education.
RT, there have been several studies investigating the addition The other obvious benefits of RCTs are access to potentially
of radiosensitizers (e.g., misonidazole and metronidazole); improved therapeutic options and contact with oncology
however, none have consistently shown benefit. Numerous scientists at the forefront of GBM treatment investigation.
alterations in the RT regimen have been studied, but none Major academic centers with active brain tumor programs
have consistently demonstrated improvements in survival, typically have numerous clinical trial options and will have
including dose escalations > 60 Gy, hyperfractionation or physicians with the specific training that is needed to care
accelerated superfractionated RT, brachytherapy, neutron versus for patients with this complex disease.
photon boosts, radioactive targeting agents, or stereotactic
radiosurgery with a linear accelerator or gamma-knife. Less 5. ‘Where we are now’
RT (50 Gy, 1.8-Gy fractions) has demonstrated a survival
advantage in patients aged > 70 years [86]. Radioenhancers Surgery has become the cornerstone in the initial treatment
such as RSR13, a synthetic modifier of hemoglobin, and of GBM, although it has not yet been validated by pro-
motexafin gadolinium are under investigation. The only major spective Phase III RCTs. Retrospective and similar-level
change in the delivery of RT that has made it to current studies show that, in general, resection > 98% doubles survival
standard-of-care treatment regimens is that coned-down or over that following biopsy alone, up to a maximum of about
focused RT is as effective as whole-brain RT, eliminating the 11 – 12 months [89-92]. GBM infiltrates adjacent brain
long-term sequelae associated with whole-brain treatment. parenchyma, so complete resection is not possible; however,
Nitrosourea studies have dominated the history of RCTs in many neuro-oncology surgeons believe that modern neu-
GBM. Meta-analysis suggests some nitrosoureas (BCNU) add roimaging allows > 98% tumor resection in cases where
a marginal benefit to survival (about 2 months) [15]. Despite tumor does not significantly involve eloquent structures
modest benefit, systemically administered BCNU universally (e.g., primary motor cortex). Only maximal cytoreduction
remained the standard of care for adjuvant chemotherapy of > 98% significantly alters survival, and probably improves
until the mid 1990s, when studies in newly diagnosed and a patient’s response to radiotherapy and chemotherapy [92,93].
recurrent GBM demonstrated a similar benefit (increasing survival by Submaximal cytoreduction may alleviate immediate mass
∼ 2 months) with BCNU (Gliadel®, Esai, Inc., Woodcliff Lake, USA) effect, causing neurological deficits or raised intracranial
administered locally to the resection cavity at the time of pressure; however, many neuro-oncology surgeons argue against
surgery [87,88]. Gliadel consists of dime-size wafers impregnated these treatment attempts because of the anticipated worse
with carmustine. Contraindications for its use include direct outcomes. Residual tumor can behave in a very aggressive
contact with eloquent cortex (e.g., primary motor cortex) or and malignant fashion, with enormous edema, and cause
critical neurovascular structures such as cranial nerves, an worse mass effect acutely when the tumor is reduced only


Table 2. Summary of all Phase III randomized clinical trials and outcomes in glioblastoma*.
RCT, year study started [ref]‡ Treatment arms (n)§ M A (y) % GBM Significant outcomes
Walker, 1966 [115] Conservative care (194), Y ND 86 RT 60 Gy increased MST to 10m over control group MST of 4m
RT <45 Gy (61),
RT 50 Gy (56),
RT 55 Gy (33),
RT 60 Gy (270)
Chin, 1966 [116] Supportive (12), N 38 – 53 56 – 80 6000 rad of whole-brain RT with surgery increased 6 m survival
BCNU (5), rate two to three times that observed in control
MeCCNU (9),
RT 6000 rad (25),
RT+MeCCNU (10),
RT+BCNU (26)
Walker, 1967 [117] RT (44), Y ND 89 No significant difference in MST with mithramycin
RT+mithramycin (52)
Walker, 1969 [96] Conservative care (42), Y 57 90 RT+BCNU increased MST to 8m from 3m in controls
BCNU (68),
RT (93),
RT+BCNU (100)
Reagan, 1970 [118] RT (22), Y ND ND No significant difference in MST with CCNU
CCNU (22)
RT+CCNU (19)
Wier, 1971 [119] RT (15), N ND ND No significant difference in MST with CCNU
CCNU (13),
RT+CCNU (13)

Solero, 1972 [120] RT 50 Gy (32), N 50 31 – 34 BCNU or CCNU increased MST from 10m – 12m and 16m,
RT+BCNU (34), respectively, when added to RT
RT+CCNU (36),
Walker, 1972 [121] RT (94), Y 55 89 RT improved MST from 7.1m – 8.5m compared to CCNU alone;
MeCCNU (81), RT+ nitrosourea increased MST to 10 – 11m
RT+BCNU (92),
RT+MeCCNU (91)
Note: RCTs are listed chronologically and include author with year of publication, breakdown of control versus treatment arms, year study began, population size, treatments, multicenter status, average age of
participants, percentage of GBM participants, treatments, and results.
*Taken from search of Cochrane Central Register of Controlled Trials (CENTRAL). Search terms included ‘glioblastoma(s)’, ‘high-grade glioma(s)’, and ‘malignant glioma(s)’. References of selected studies were used to
identify additional trials.
‡Most studies reported start of patient accrual. For those that did not, the publication year was stated.
§The first listed treatment arm is the control arm for the study.
5-ALA: 5-Aminolevulinac acid; A: Age (range in mean age for each treatment group); ACNU: Nimustine; ART: Accelerated RT; BCNU: Carmustine; CCNU: Lomustine; CED/Ch81C6: Convection-enhanced delivery of
human-murine chimeric monoclonal antitenascin antibody Ch81C6; DBD: Dibromodulcitol; DTIC: Dacarbazine; DTI-NN: Diffusion tensor imaging-based functional neuronavigation; %GBM: Range in percentage of GBM
for each treatment group; Gy: Gray; HD-MP: High-dose methylprednisolone; HRT: Hyperfractionated RT; HSVTK/G: Herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy; HU: Hydroxyurea;
IRT: Interstitial RT; m: Months; M: Multicenter; MeCCNU: Semustine; METRO: Metronidazole; MISO: Misonidazole; MST: Median survival time; n: Number per group; ND: Not enough data to determine; PCB: Procarbazine;
PCNU: Piperidine nitrosourea; PCV: Procarbazine/vincristine/lomustine; RT: External beam radiotherapy; SRT: Superfractionated RT; TEMO: Temozolomide; VM26: Teniposide; y: Year.
1067
Table 2. Summary of all Phase III randomized clinical trials and outcomes in glioblastoma* (continued).
1068
EORTC, 1973 [122] RT (59), Y ND 69 RT+CCNU increased MST from 10 – 14m compared with RT
RT+CCNU (52) alone.
Chang, 1974 [89] RT (148), Y 55% were 66 – 71 Preliminary report of study. No significant difference between
RT+booster RT (105), 40 – 59 control and treatment arms in MST
RT+BCNU (165),
RT+MeCCNU+DTIC (136)
Hatlevoll, 1974 [123] 8 arms testing RT 40 Gy, Y 51 – 56 ND No significant difference in MST between all arms
RT 50 Gy, MISO, CCNU;
control was RT alone
(244 total)
Urtasan, 1974 [124] RT (15), N ND 100 Metronidazole increased MST from 3.5 – 6m, making tumor
RT+high-dose metronidazole cells more radiosensitive
Kristiansen, 1974 [95] Conservative care (38), Y ND ND RT improved MST; no significant increase in MST with bleomycin
RT+placebo (35),
RT+bleomycin (45)
Eyre, 1974 [125] RT+CCNU (56), Y ND 75 No significant increase in MST with PCB
RT+CCNU+PCB (59)
Nelson, 1974 [126] RT 60 Gy (141), N ND 72 – 77 Overall, no significant difference when adding RT boost, BCNU,
RT 60 Gy+10 boost (103), CCNU, or DTIC; 40- to 60-y-old patients had increased 2-y
RT 60 Gy+BCNU (156), survival from 8 – 23% when BCNU was added to RT
RT 44 Gy+MeCCNU+
DTIC (138)

Bleehen, 1976 [127] RT 56 Gy (20), N 50 – 58 31 – 35 No significant increase in MST with MISO radiosensitizer
RT 44 Gy (18),
RT 44 Gy+MISO (17)
Urtasun, 1976 [128] RT (19), N 58 75 No significant increase in MST with metronidazole or MISO
HRT+ metronidazole (17), radiosensitizer
HRT+MISO (23)

Green, 1976 [129] RT+BCNU (147), Y ND 87 The addition of BCNU or PCB increased MST from
RT+HD-MP (156), 9m to 11m. HD-MP did not increase MST
RT+PCB (153)
RT+BNCU+HD-MP (153)
Payne, 1977 [130] RT (79), N ND ND No significant difference in MST with hyperfractionated RT
SRT (78)
Griffin, 1977 [131] RT 50 Gy+photon Y ND ND No significant difference in MST between neutron or photon
boost (83), boost
RT 50 Gy+neutron
Boost (83)
Eyre, 1977 [132] RT+BCNU (82), Y 55 84 BCNU or DTIC increased MST to 11m when compared to PCB (7m)
RT+PCB (83),
RT+DTIC (78)
Afra, 1978 [133] RT (32), Y ND 63 DBD increased MST from 9m – 13m when compared to RT alone.
RT+DBD (28), CCNU added no significant benefit over DBD
RT+DBD+CCNU (31)
Shin, 1978 [134] RT+CCNU (34), N 54 ND SRT (3 fractions/day) improved MST from 9 – 13m
SRT+CCNU (35)
Deutsch, 1978 [135] RT+BCNU (152), Y ND 86 No significant difference in MST with MISO or HRT
RT+streptozocin (146),
HRT+ BCNU (154),
RT+MISO pre-BCNU (151)

MRC, 1979 [136] RT+Placebo (196), Y ND 58 No significant difference in MST with MISO
RT+MISO (188)
Nelson, 1979 [137] RT+BCNU (146), Y ND 83 No significant difference in MST with MISO
RT+BCNU+MISO (147)
Takakura, 1980 [138] RT (37), Y ND 58 No significant difference in MST with ACNU
RT+ACNU (40)
1069
1070
Shapiro, 1980 [139] RT+BCNU (114), Y ND 80 Coned-down RT as effective as whole brain RT. PCB, HU, VM26
RT+BCNU+PCB (176), did not improve MST
RT+BCNU+HU+VM26 (168)
Elliott, 1980 [140] RT+BCNU (114), Y ND 63 No significant difference in MST between BCNU and DBD
RT+DBD (115)
EORTC, pre-1981 [141] RT (55), Y 39% < 50 30 No significant difference in MST between all arms
RT+CCNU+VM26 early (61)
RT+CCNU+VM26 late (21)
Mahaley, 1981 [142] RT+BCNU (25), N 53.2 76 No significant difference in MST with addition of PCB, HU, or
RT+BCNU+PCB (28), VM26
RT+BCNU+HU/PCB+ VM26 (28)
Ludgate, 1981 [143] RT (34), N 55.5 ND Early benefit (MST increased from 7.4m – 10.6m), but no late
SRT (42) benefit
Sandberg-Wollheim, 1981 [144] PCV (71), N ND 47 For patients < 50y old, RT+PCV increased MST from 10.8m – 15.2m
RT+PCV (68) when compared to PCV alone
Levin, 1977 [145] RT/HU+BCNU (66), Y 41 – 57 44 – 46 No significant difference in MST between arms for GBM
RT/HU+PCV (67)
Bleehen, 1983 [146] RT 45 Gy (156), Y ND 67 60 Gy increased MST from 9 – 12m when compared with 45 Gy
RT 60 Gy (318)
Shapiro, 1983 [147] RT+Intravenous BCNU (126), Y ND 75 MST decreased with intra-arterial BCNU with significant toxicities
RT+Intra-arterial BCNU (153)

Dinapoli, 1985 [148] RT+BCNU (166), Y ND 71 No significant difference in MST with PCNU, with worse
RT+PCNU (168) toxicities
MRC, 1985 [149] RT (339), Y ND 81 No significant difference in MST with PCV
RT+PCV (335)
Selker, 1987 [150] RT+BCNU (137) Y ND 85 No significant difference in MST with IRT boost
RT+IRT boost+BCNU (133)

Trojanowski, pre1988 [151] RT (104), Y 53% ≤ 50 41 No significant difference in MST with CCNU
RT+CCNU (94)
Pickles, 1988 [152] RT ( 41) Y ND 83 No significant difference in MST with pion RT
Pion RT (40)
Hildebrand, 1989 [153] RT (134), Y ND 77 DBD+BCNU increased MST from 10m – 13m when compared
RT+DBD+BCNU (135) with RT alone
Valtonen, 1992 [154] Placebo implant+RT (16), Y ND 85 Gliadel significantly increased MST from 9.2m to 13.4m
Gliadel implant+RT (16)
Weller, 1994 [155] RT+ACNU+VM26 (183), Y ND 83 No significant difference in MST between VM26 and Ara-C
RT+ANCU+Ara-C (179)
Buckner, 1994 [156] RT+BCNU (98), Y 55 – 56 95 – 99 No difference in MST between cisplatin and control arms.
ART+BCNU (103), Cisplatin produced more toxicity. RT and ART produced similar
RT+BCNU+cisplatin (100), toxicity
ART+BCNU+cisplatin (100)
Levin, 1996 [157] RT+placebo (79), Y 57 – 58 95 No significant difference in MST with marimastat
RT+Marimastat (83)
Rainov, 1996 [158] RT (124), Y 59 96 No significant difference in MST with gene therapy
RT+HSVTK/G (124)
Grossman, 1996 [159] RT+BCNU (110), Y ND 99 No significant difference in MST with cisplatin given before RT
BCNU+cisplatin pre-RT (109)
Westphal, 1997 [88] Placebo implant+RT (120), Y ND 99 Gliadel increased MST from 11.6m – 13.9m

Gliadel implant+RT (120)
Willems, 1999 [160] Surgery (36), N 60 69 No difference in amount of resection or MST
Surgery+neuronavigation (26)
Combs, 1999 [161] RT+50mg/m TEMO (123), N 57 – 61 100 No difference in overall survival with lower-dose TEMO
RT+75mg/m TEMO (37)
1071
1072
Stupp, 2005 [99] RT (286) Y ND 97 Concomitant TEMO+RT increased MST from 12.1m – 14.6m
RT+TEMO (287)
Stummer, 2000 [113] Surgery (161), Y 60 98 Tumor fluorescence improved tumor resection and 6-m survival.
Surgery+5-ALA (161)
Sotelo, 2000 [162] RT+BCNU (15), N 40 – 46 100 Chloroquine increases MST from 11m to 24m compared with
RT+BCNU+chloroquine (15) controls (different pre-treatment characteristics).
Keime-Guibert, 2001 [86] Supportive care alone in Y 73 – 75 96 RT increased MST from 4.2m – 7.3m when compared to
>70y-old patients (42), supportive care only in patients ≥ 70 y old.
Supportive care +RT in
>70y-old patients (39)
Wu, 2001 [163] Surgery (120), N 38 – 41 21 DTI-NN increased resection, decreased postoperative deficits,
Surgery+DTI-NN (118) increased MST
Imbesi, pre-2005 [164] Intravenous ACNU (16), N 54 – 58 100 No difference in toxicity or survival
Intra-arterial ACNU (17)
Henriksson, pre-2006 [165] RT (63), Y 55 62 No difference in MST with estramustine
RT+estramustine (59)
Sampson, pre-2006 [166] Bolus CED/Ch81C6 (6), N ND 100 No difference in distribution of drug. Survival not evaluated
Infused CED/Ch81C6 (3)

Wygoda, pre-2006 [167] RT (10), N 47 – 52 72 No difference in survival with 125I-EGFR antibody
RT+125I-EGFR antibody (8)
partially. Yet maximal cytoreduction appears to improve survival Recurrent tumor, which happens virtually 100% of the
only in the short term. As seen in a recent meta-analysis, 2-year time, is clearly more difficult to treat. These patients may be
disease-free survival is unchanged in patients who receive considered for cytoreductive surgery again if they have a
maximal cytoreductive surgery versus biopsy alone [15]. Patients good KPS and a biopsy has ruled out radiation necrosis,
who undergo surgery at high-volume academic centers appear which can easily mimic recurrent tumor. Numerous studies
to have an advantage, as mortality at these centers is half have looked at recurrent GBM (Table 2), but no standard of
(2.5%) of that seen at low-volume centers (4.9%) [94]. care for recurrent tumor has been established. Gliadel may
RT has also been shown to add several months to survival, be considered. Based on the available evidence, most
and has become part of the standard of care. Currently, neuro-oncologists recommend TMZ re-challenge in patients
postoperative fractionated external-beam radiotherapy is rou- who did not progress while on TMZ or another
tine. It is administered as 60 Gy in 30 fractions over a period nitrosourea-based chemotherapy. RT is usually not an
of about 6 weeks to a target volume defined as a 2- to 3-cm option, since most patients will have undergone the full
ring of tissue beyond the contrast-enhancing rim of tumor course during initial presentation. As seen with newly diag-
seen on the preoperative MRI or CT scan. All enhancing nosed GBM, patients with recurrent tumor should also be
tumor is ideally resected and not visible on postoperative considered for clinical trials, due to the benefits associated
neuroimaging. RT should not be started before 2 weeks with participation.
after surgery, to allow for adequate wound healing. Phase III
RCTs have shown that RT can prolong survival after surgery 6. ‘Where we are going’
to 9 – 10 months, doubling the 4 – 5 months’ survival of
patients who receive only supportive care after surgery [95,96]. Despite our tremendous breadth and depth of understanding
Whole-brain RT is typically used for multifocal GBM, such in the oncogenomics and molecular biology of GBM, the
as gliomatosis cerebri. overwhelming majority of successful preclinical therapies
Chemotherapy has seen the longest, most varied, and have failed to provide meaningful results at the clinical stage
most disappointing history in laboratory and clinical of testing. There are several possible reasons for our current
research, with numerous RCTs dating to the 1970s (Table 2). treatment failures. However, significant knowledge gained
Meta-analyses looking at various heterogeneous chemotherapy from these, together with new insight into the molecular
regimens show an overall survival benefit of an additional biology of GBM, has provided new directions for where we are
1 – 2 months. Therefore, in combination with surgery and RT, going with future therapeutic studies. In addition to numerous
chemotherapy provides an overall median survival of about surgical tools and radiation strategies under study, current
14 months. However, this probably includes significant chemotherapeutic strategies under study cover a broad array
selection biases and improved outcomes for patients involved of treatments and approaches (Table 3 and Figure 2). The
in clinical trials [15,97]. Despite this long history, only two most common types of chemotherapies under investigation
agents have made their way into standard-of-care treatments include targeted molecular therapies, antiangiogenic therapies,
for newly diagnosed and recurrent GBM: Gliadel and temo- immunotherapies, gene therapies, radiation-enhancement
zolomide (TMZ), both of which separately increase survival therapies, and drugs to overcome resistance (Table 3 and
by about 2 months [88,98,99]. TMZ is an imidazotetrazine Figure 2) [101-104].
derivative of the alkylating agent dacarbazine. It gets con- One well-known reason for failure of the standard
verted in the systemic circulation at physiologic pH to the chemotherapy in use today, TMZ, is the presence of
active compound monomethyl triazone imidazole carboxam- DNA repair enzymes, namely MGMT as described above.
ide (MTIC). It exhibits schedule-dependent antineoplastic Techniques for circumventing this DNA protective enzyme
activity by interfering with DNA replication. Like most may make TMZ more effective and are under active
prior GBM chemotherapies, it acts nonspecifically on rap- investigation (Table 3). Dose-intensive TMZ to quickly
idly dividing cells, but has the benefit of some crossing of deplete MGMT, combinations of TMZ with MGMT
the blood–brain barrier and much less toxicity. TMZ should inhibitors (e.g., O6-benzylguanine), or combinations of
be administered concomitantly with RT at 75 mg/m2 daily TMZ with other DNA repair enzyme inhibitors (e.g.,
followed by 200 mg/m2 for 5 days every 4 weeks for a total poly-ADP-ribose-polymerase) are being studied [105].
of 6 months [99]. Patients with methylation (and therefore As mentioned above, there appear to be multiple, redundant
silencing of gene expression) of MGMT that confers resis- signaling pathways in GBM. Therefore, the upstream location
tance to alkylating agents respond better to TMZ [100]. The of targets (e.g., growth factor receptors) makes the drugs
efficacy of the combination of BCNU and TMZ has not that target them susceptible to downstream resistance due to
been established, nor has any RCT consistently shown any other factors driving the pathway of interest. This implies
benefit to pre-RT chemotherapy. Antiangiogenic agents have that combination therapies may be required to significantly
shown the most success of recently explored chemotherapies, target a specific pathway, or a combination of important
with bevacizumab recently obtaining FDA approval for use pathways [106]. Recent clinical trials have already begun
in GBM. exploring combination therapies. For example, a Phase II

Table 3. Current clinical trials for investigational drugs in glioblastoma.
Type of treatment strategy and target Investigational agents
Small molecule targeted therapies

AKT inhibitor Perifosine
EGF RTK inhibitor Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab,
cetuximab, AEE788
Growth factor inhibitor Leflunomide, suramin
FTI inhibitor Tipifarnib, lonafarnib
HDAC inhibitor Vorinostat, depsipeptide, panobinostat, romidepsin
HSP90 inhibitor AT13387
LDL receptor peptide ANG1005 (taxane derivative targets LDL receptors)

Met inhibitor XL184
MMP inhibitor Prinomastat
Microtubule disruption CYT997, MPC-6827, epothilones
mTOR inhibitor Everolimus, sirolimus, temsirolimus, deforolimus, rapamycin
PDGF RTK inhibitor Dasatinib, imatinib, tandutinib, pazopanib
PI3K inhibitor BEZ235, XL765
PKCβ STK inhibitor Enzastaurin
Proteosome inhibitor Bortezomib
Raf inhibitor Sorafenib
Ras inhibitor TLN-4601

Sp1 inhibitor Terameprocol
Src TK inhibitor Dasatinib
TGFβ inhibitor AP12009 (antisense)
Topoisomerase inhibitors RTA744, etoposide, topotecan, irinotecan, AQ4N, edotecarin,
rubitecan, pyrazoloacridine, karenitecin, gimatecan
VEGF RTK inhibitor PTK787, semaxanib
Others 131I-TM601 (scorpion venom peptide), CC-8490
Antiangiogenic therapies
Anti-αvβ5 integrins Cilengitide, ATN-161
Anti-hepatocyte GF AMG-102
Anti-VEGF Bevacizumab, aflibercept (VEGF-Trap)
Anti-VEGFR Cediranib, pazopanib, sorafenib, sunitinib, vandetanib,
vatalanib, XL184, CT-322
Others Thalidomide, lenalidomide, atrasentan (endothelin- A
receptor antagonist), ABT-510
Immunotherapies
Bispecific antibodies MDX447 (EGFR and CD64)
Cytokine-mediated Cintredekin besudotox (IL13-PE38QQR), PRX321 (IL-PE),
NBI-3001 (IL4- PE38KDEL), aldesleukin (IL2 analog)
Dendritic cell vaccines DC pulsed with tumor cell lysates (DCVax) EGFRvIII
peptide (CDX-110), tumor stem cell mRNA
Note: Summary of 498 currently active clinical trials for glioblastoma in the United States (clinicaltrials.gov).
CpG ODN: Cytosine-guanine island oligodeoxynucleotides; DC: Dendritic cells; EGF: Epidermal growth factor; FTI: Farnesyl transferase inhibitors; GF: Growth
factor; HDAC: Histone deacetylase; HSP: Heat shock protein; IL: Interleukin; LDL: Low-density lipoprotein; MGMT: Methylguanine methyltransferase; MMP: Matrix
metalloproteinase; PARP: Poly-(ADP ribose)-polymerase; PDGF: Platelet derived growth factor; PE: Pseudomonas exotoxin; RTK: Receptor tyrosine kinase;
STK: Serine-threonine kinase; TK: Tyrosine kinase; TMZ: Temozolomide; VEGF: Vascular endothelial growth factor.

Table 3. Current clinical trials for investigational drugs in glioblastoma.
Type of treatment strategy and target Investigational agents
Immunostimulatory GM-CSF + PEP-3-KLH (EGFRvIII peptide), Lyphokine-activated

killer cells, CpG ODN (activate dendritic and B cells),
autologous tumor cell vaccine, Poly ICLC (toll-like
receptor 3 ligand), vitespan (patient-specific HSPgp96
vaccine), Immuncell-LC (activated T cells)
Immunotoxin Transferrin-CRM107 (transferrin + diphtheria), TP-38

(TGFα + PE)
Radiolabeled antibodies 131I-anti-tenascin antibody (81c6), Cotara (TNT-1/B, 131I–
labeled tumor necrosis antigen antibody), Astatine

At211-anti-tenascin antibody (81c6)
Gene therapies
Adenovirus vector Recombinant adenovirus-hIFNb, ADV-TK (ADV-HSV thymidine

kinase) + valacyclovir, ADV-p53 (SCH-58500), Ad5CMV-p53
Cytokine genes IFNb gene transfer
Oncolytic viruses G207 (herpes simplex virus I)
Reovirus mediated Reolysin (targets Ras-activated cells)
Drugs for TMZ resistance
Dose-dense TMZ TMZ

MGMT inhibitors O6-benzylguanine
PARP inhibitors BSI-201, ABT-888

Note: Summary of 498 currently active clinical trials for glioblastoma in the United States (clinicaltrials.gov).
CpG ODN: Cytosine-guanine island oligodeoxynucleotides; DC: Dendritic cells; EGF: Epidermal growth factor; FTI: Farnesyl transferase inhibitors; GF: Growth
factor; HDAC: Histone deacetylase; HSP: Heat shock protein; IL: Interleukin; LDL: Low-density lipoprotein; MGMT: Methylguanine methyltransferase; MMP: Matrix
metalloproteinase; PARP: Poly-(ADP ribose)-polymerase; PDGF: Platelet derived growth factor; PE: Pseudomonas exotoxin; RTK: Receptor tyrosine kinase;
STK: Serine-threonine kinase; TK: Tyrosine kinase; TMZ: Temozolomide; VEGF: Vascular endothelial growth factor.
trial of an antiangiogenic antibody, bevacizumab, combined Many of these are in trials of combination therapies. This
with a topoisomerase I small molecule inhibitor, irinotecan, approach offers the advantage of remarkable specificity,
showed efficacy in recurrent GBM [107]. Understandably, reduced toxicity, and applicability to other cancers with
older studies focused on proteins overexpressed on the surface similar aberrant signaling cascades.
of GBM cells as promising targets. Antibodies directed at Recent clinical trials have shown great promise with
EGFR and its mutated variants have been studied for many antiangiogenic therapies in this highly vascular tumor. Current
years, but they have not quickly translated into effective investigational antiangiogenic therapies consist of antibodies
therapies. More work is being done. The more recent eluci- directed toward factors such as αvβ5 integrins (cilengitide),
dation of the aberrant signaling pathways and their redundant, hepatocyte growth factor (AMG-102), VEGF (bevacizumab),
cross-talking factors (e.g., mTOR) have now moved a signifi- and VEGFR (sunitinib). Because of its clinical success, beva-
cant amount of focus toward studying small molecules that cizumab will probably be the next antiangiogenic agent
can directly target these downstream factors (Table 3). Numerous approved by the FDA for recurrent GBM [107-110]. Some of
commonly studied signaling factors are now being targeted these therapies have the advantage of directly targeting
by investigational drugs in modern clinical trials (Figure 2). tumor vasculature, as well as tumor cells directly. The pri-
Therapies directed at unique proteins are typically small mary concern of these therapies is the possible increased risk
molecule inhibitors. These agents target factors such as Akt of intracranial hemorrhagic complications. Current studies
(perifosine), EGFR (erlotinib), farnesyl transferase (lonafarnib), (Table 3) will help determine the efficacy and risk profile of
histone deacetylase (vorinostat), heat shock proteins (AT13387), these exciting therapies.
Met (XL184), mTOR (sirolimus), PI3K (BEZ235), PKCβ As alluded to above, we now know that the altered
(enzastaurin), PDGFR (imatinib), proteasomes (bortezomib), immune environment in GBM probably contributes to tumor
Raf (sorafenib), Src (dasatinib), and TGF-β (AP12009). progression and hampers therapies. Numerous exciting and

varied investigational immunotherapies for GBM are now vectors are the most commonly used in studies today to
being pursued, including passive, active, and adoptive immu- deliver suicide genes such as thymidine kinase, or tumor
notherapeutic approaches (Table 3). Passive immunotherapy suppressor genes such as p53. Most recently, results of
involves administering antibodies or toxins to patients without genetic studies indicate that the next era of RCTs in GBM
specifically inducing or expanding a host antitumor response. is likely to focus on using extensive gene expression databases
Examples of antibodies currently under study include iodine to better characterize these deadly tumors and design more
131-labeled antitenascin antibody (also known as 81C6), efficacious targeted therapies.
astatine 211-labeled antitenascin antibody, and the bispecific A very exciting area of study in GBM, and indeed in all
anti-EGFR and anti-CD64 antibody. Immunotoxin therapies cancers, is tumor stem cell biology. Now that the existence
include transferrin-CRM107 (transferrin conjugated with of this special tumor cell population has been confirmed,
diphtheria toxin) and TP-38 (TGF-α conjugated with additional studies are required to further our understanding
Pseudomonas exotoxin). These passive immunotherapies all of the biology of these cells. We do know that glioma stem
target proteins overexpressed on the surface of glioma cells. cells (GSCs) appear to be remarkably resistant to current
TP-38 represents an elegant example of molecular engineering. radio- and chemotherapies, probably due to genomic and
This immunotoxin is a recombinant chimeric protein proteomic profiles that differ from the larger non-GSC
composed of the EGFR binding ligand, TGF-α and a population. Future therapies will have to effectively attack
genetically engineered Pseudomonas exotoxin. Once this pro- this small population of cells in order to impact upon the
tein binds cells expressing EGFR, a domain of the exotoxin disease outcome. This will clearly be a very exciting area of
undergoes proteolytic cleavage and mediates translocation of investigational drug design in the near future.
the carboxyl terminal toxin into the cytosol. Another domain GBM universally recurs due to proliferation of cells that
of the exotoxin contains an adenosine 5′-diphosphate (ADP) have migrated away from the tumor focus. Current therapies
ribosylating activity that inactivates elongation factor 2, have significant difficulty targeting these cells. Surgical resec-
resulting in the death of the cell. In active immunotherapy, tion and local chemotherapies (e.g., Gliadel wafers placed in
the tumor-bearing host is immunized with a ‘vaccine’ to the resection cavities) are unlikely to target migrated cells.
expand an antitumor immune response in vivo, whereas Investigators are using agents such as D-aminolevulinic acid
adoptive immunotherapy employs the ex vivo expansion of to fluorescently label tumor cells to help assist surgeons dur-
effector cells and return of these effectors to the tumor- ing resection [113]; however, strategies such as this are also
bearing host. Examples of active immunotherapies include unlikely to allow surgeons to remove all tumor cells that
autologous tumor cell vaccines, vitespen (heat shock protein have migrated away. Convention enhanced delivery (CED)
gp96 vaccine), and PEP-3-KLH (EGFRvIII peptide conjugated methods allow therapies to be infiltrated into localized areas
to immunostimulatory agent). Exciting adoptive immuno- of brain parenchyma, potentially as large as an entire cerebral
therapy strategies include various dendritic cell vaccines. In hemisphere. Curative therapies will have to be able to cross
these complex treatments, autologous dendritic cells are iso- the highly selective blood–brain barrier, infiltrate throughout
lated from patients, pulsed with tumor-specific molecules the entire brain, and specifically attack migrating cells without
(e.g., tumor-specific peptides [EGFRvIII], tumor cell lysates, harming surrounding normal brain. Our current knowledge
tumor stem cell mRNA), expanded ex vivo, and then rein- of GBM suggests a progressive accumulation of genomic and
troduced to the patient [111] This field of investigation has slowly proteomic changes. This is clearly evident in the multitude of
moved from nonspecific immunostimulatory approaches differences between primary and secondary GBM. However,
toward efforts eliciting very specific immune responses it is not unreasonable that the progressive nature of genomic
against tumor antigens, either by use of active immunization instability of these tumors never stops. Successful therapies
(cancer vaccines) or adoptive transfer of tumor-specific effector will have to work quickly and thoroughly; recurrent tumors
cells or antibodies (adoptive immunotherapy) [112]. may require re-evaluation for different therapies due to a
Gene therapies experienced a surge of interest in the new genomic and proteomic profile.
1990s as genomic research tools became more available and
cheaper and the Human Genome Project approached com- 7. Conclusion
pletion. Directly inhibiting the expression of oncogenes and
normalizing the expression of tumor suppressor genes has In summary, the current recommendations for therapy are
always been very appealing; however, the appearance of gene that all newly diagnosed GBM patients should be initially
therapy approaches in clinical trials has not kept pace with considered for cytoreductive surgery (> 98%), concurrent
studies of small-molecule protein inhibitors or antiangio- TMZ/RT 2 – 6 weeks after surgery, and then TMZ for
genic drugs. Gene delivery mechanisms are still being opti- 6 months. Recurrent tumor patients with a good KPS
mized. Several viral vectors (herpes simplex, adenovirus, and should be considered for resection again, followed by TMZ
poliovirus), nanoparticle constructs, expression plasmids, or a nitrosourea, and RT if they did not previously receive
and liposomal preparations to deliver numerous genes into the maximal tolerated dose. Bevacizumab is likely to be
tumor cells are still under study. Of these strategies, adenoviral approved by the FDA for recurrent disease in the near future,

and if so it will become part of standard care for recurrent and TMZ. This will be improved upon with the current
disease. These patients may benefit from a judicious use of surge of investigational drugs.
corticosteroids to alleviate mass effect due to vasogenic
edema. These should be tapered off as quickly as possible, since 8. Expert opinion
increased doses are likely to be needed during surgery or RT.
Patients experiencing seizures should receive appropriate Glioblastoma remains one of the most common and most
antiepileptic drugs (AED), but these should be carefully malignant primary CNS tumors in humans. It continues to
considered, since enzyme-inducing AED can alter the efficacy be a largely histologically diagnosed disease, even though
of chemotherapies. Because of the benefits of clinical trials, ample evidence demonstrates tremendous genomic and
all patients should be referred to academic centers with proteomic heterogeneity. From this thorough review of ‘where
active clinical studies. Patients should be followed closely we have been’ and ‘where we are going,’ it is clear that an
(every 2 months with imaging) for the late sequelae of these enormous degree of investigation has been devoted to this
aggressive treatments, such as cognitive deficits, electrolyte universally fatal disease. Unfortunately, almost half a cen-
abnormalities, and deep venous thrombosis. Fortunately, tury of investigation has not drastically altered survival.
there is significant hope for future therapies. Numerous Evidence supports continuation of an initial attempt to
promising areas of clinical investigation are underway achieve > 98% tumor resection. When not involving elo-
(Table 3 and Figure 2) in diverse areas. Promising active areas quent cortex, we believe this should be an achievable goal of
of clinical study include small molecular inhibitors (e.g., all neuro-oncology surgeons. RCTs have also proven that
everolimus, which targets mTOR), antiangiogenesis agents postsurgical concomitant RT and TMZ will increase survive
(e.g., anti-VEGF antibodies), novel immunotherapeutic by 2.5 months, up to about 14 months. Even though other
approaches (e.g., dendritic cell vaccines stimulated with chemotherapies, namely nitrosoureas, have shown similar
tumor-specific antigens, peptide vaccinations), growth factor marginal benefit, TMZ should be the first-line postsurgical
receptor targeting (e.g., radiolabeled anti-EGFRvIII antibodies), chemotherapy because of its ease of administration, low
gene therapies, strategies to overcome drug resistance, and toxicity profile, and proven benefit. Intraoperative place-
combination therapies for specific molecular targets (e.g., ment of Gliadel when appropriate is also considered by
topoisomerase, mTOR, and kinase inhibitors). More and more some to be standard of care. Gliadel has been demonstrated
studies are looking at pediatric patients as well, with recent in RCTs to show similar survival benefit as TMZ; however,
studies suggesting that they may have their own unique the benefit of the combination of these two therapies is still
genetic expression profiles and signaling pathways [114]. TMZ unclear and needs further rigorous investigation. Despite
is being studied in several studies in combination with other these various therapies, the current outcome remains dismal
cytotoxic or cytostatic agents to improve current treatment for these patients. Therefore, all patients should be rou-
schedules, or in studies to explore mechanisms to overcome tinely referred to institutions with active clinical trials, since
chemotherapy resistance. There is real hope that the near this also provides survival benefit. Young age and high KPS
future will see more effective targeted therapies, perhaps continue to be the strongest positive predictors of survival;
even designed to meet the needs of individual patients. these factors should be taken into consideration during
Glioblastoma has a long history of clinical investigation counseling, when referring patients for additional therapy,
that has shaped our current understanding of this fatal disease. and when treating tumor recurrence. If possible, recurrence
In all of oncology, it remains a relatively uncommon tumor, should be treated with resection and adjuvant TMZ.
but is the most common primary CNS tumor encountered. Appropriate care of these patients should involve a multi-
Even though the number of studies of this disease has grown disciplinary team: neurosurgeon, neuro-oncologist, and
almost exponentially, we are still awaiting breakthroughs radiation oncologist. There should also be mechanisms for
that can extend survival beyond the typical 14 months. assisting these patients with quality-of-life issues as the
There are currently no common, easily identifiable etiologies disease progresses. Involvement in institutions with dedicated
or risk factors, except for ionizing radiation and inherited brain tumor centers can offer significant benefits to these
syndromes; however, a complete unraveling of the GBM patients, since these centers often have individuals dedicated
genome may provide important clues in the near future. to helping oncology patients with the long-term care issues
Because of the rapidity of its progression, GBM typically results that inevitably arise.
in symptoms at presentation that lead to is radiographic and With the explosion in gene expression profiling, signaling
pathologic diagnosis. Histopathologic descriptions have pathway characterization, GSC identification, and immuno-
remained unchanged for decades, but are likely to be com- modulation strategies in GBM that has occurred over the last
plemented by relevant genetic alterations, e.g., MGMT decade, there is now a tremendous surge in clinical studies
methylation status, as we gain a better understanding of the evaluating new agents. In the next 5 – 10 years, these will
oncogenomic events and signaling pathways unique to be the major areas of investigational drug studies for
GBM. During the past 5 years, we have witnessed a new GBM: specific molecular targeting, antiangiogenic therapies,
postoperative standard of care that includes concomitant RT immunotherapies, gene therapies, drugs to overcome resistance,

and combination therapies. We will see major advances in help to determine whether ‘personalized cancer treatments’
the understanding of glioma stem cells and migrating tumor will become the norm, or if we will successfully identify
cells. The results from Phase III RCTs of these exciting common targets.
new areas of investigation will soon begin appearing, and
will help to ascertain which of these therapeutic strategies Declaration of interest
holds the greatest promise. The oncogenomic heterogeneity
in oncology has supported the original belief that future The authors state no conflict of interest and have received
therapies will be individually tailored. The near future will no payment in preparation of this manuscript.
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Glioblastoma multiforme: A review of where we have been and where we are

Article in Expert Opinion on Investigational Drugs · June 2009

Okezie Obasi Kanu Ankit I Mehta

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Chunhui Di Darell D Bigner

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UIC-Duke Brain Tumor Study View project

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and signaling pathways, tumor stem cell identification and characterization,

Keywords: GBM, genetics, glioblastoma multiforme, oncogenomics, signaling cascades

Expert Opin. Investig. Drugs (2009) 18(8):1061-1083

1. Overview of glioblastoma

10.1517/13543780903052764 © 2009 Informa UK Ltd ISSN 1354-3784 1061

All other astrocytomas,

1062 Expert Opin. Investig. Drugs (2009) 18(8)

15 of this deadly tumor.

Expert Opin. Investig. Drugs (2009) 18(8) 1063

variant III (EGFRvIII), which is present in 20 – 50% of

1064 Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Anti-αvβ5 antibody Anti IL13 antibody Anti-Tenascin antibody131I-81c6

1066 Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8) 1073

Table 3. Current clinical trials for investigational drugs in glioblastoma.

Type of treatment strategy and target Investigational agents

Small molecule targeted therapies

LDL receptor peptide ANG1005 (taxane derivative targets LDL receptors)

Ras inhibitor TLN-4601

1074 Expert Opin. Investig. Drugs (2009) 18(8)

Table 3. Current clinical trials for investigational drugs in glioblastoma.

Type of treatment strategy and target Investigational agents

Immunostimulatory GM-CSF + PEP-3-KLH (EGFRvIII peptide), Lyphokine-activated

Immunotoxin Transferrin-CRM107 (transferrin + diphtheria), TP-38

Radiolabeled antibodies 131I-anti-tenascin antibody (81c6), Cotara (TNT-1/B, 131I–

labeled tumor necrosis antigen antibody), Astatine

Adenovirus vector Recombinant adenovirus-hIFNb, ADV-TK (ADV-HSV thymidine

Cytokine genes IFNb gene transfer

Oncolytic viruses G207 (herpes simplex virus I)

Reovirus mediated Reolysin (targets Ras-activated cells)

Drugs for TMZ resistance

Dose-dense TMZ TMZ

MGMT inhibitors O6-benzylguanine

PARP inhibitors BSI-201, ABT-888

Expert Opin. Investig. Drugs (2009) 18(8) 1075

1076 Expert Opin. Investig. Drugs (2009) 18(8)

Expert Opin. Investig. Drugs (2009) 18(8) 1077

Bibliography 8. Schrock E, du Manoir S, Veldman T, United States, 1977-2000. Cancer

Papers of special note have been highlighted

1078 Expert Opin. Investig. Drugs (2009) 18(8)

2007;130(Pt 10):2596-606 1998;21(4):340-6 carmustine. Cancer Res 1996;56(4):783-8

Expert Opin. Investig. Drugs (2009) 18(8) 1079

in human glioblastoma. Oncogene tumors. VI. Suppressor cell function and

1080 Expert Opin. Investig. Drugs (2009) 18(8)

98. Brem H, Piantadosi S, Burger PC, survival in malignant astrocytoma patients

•• Established a new standard of care for neurofibromatosis gene: identification

Expert Opin. Investig. Drugs (2009) 18(8) 1081