Glioblastoma Multiforme - Past, Present, and Future
Andrew B Lassman, MD1 and Eric C Holland, MD, PhD1–3 Departments of 1. Neurology; 2. Surgery (Neurosurgery); and 3. Cancer Biology & Genetics, Memorial Sloan-Kettering Cancer Center
Brain Cancer
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a report by
Andrew B Lassman, MD1 and Eric C Holland, MD, PhD1–3
Departments of 1. Neurology; 2. Surgery (Neurosurgery); and 3. Cancer Biology & Genetics,
Memorial Sloan-Kettering Cancer Center
Past
The most common cancer arising from the brain is the
glioblastoma multiforme (GBM). It is also the most
deadly, representing the most aggressive subtype among
the gliomas,a collection of tumors including astrocytomas
and oligodendrogliomas. In 1926, Bailey and Cushing, in
describing ‘spongioblastoma multiforme’, the label then
used for GBM, noted that:
“It is from this group doubtless that the generally
unfavorable impression regarding gliomas as a whole has
been gained. It is not only the largest single group in the
series…but at the same time is one of the most
malignant…In the five unoperated cases, the average
duration of life from the onset of symptoms was only
three months, which speaks well on the whole for the
average survival period of twelve months for those
surgically treated.”
Since their seminal work, the median survival of 12
months has not changed markedly. Both data from the
1960s and current data confirm that the extent of surgical
resection is an important prognostic factor. However, as
Bailey and Cushing observed, GBMs have “infiltrating
propensities, and…when enucleation is attempted, the
growth is found at the depth to spread into and merge
with the normal cerebral tissue without recognizable
demarcation. In prior eras, radical surgical excisions,
including removal of the entire cerebral hemisphere
containing the tumor, were occasionally attempted, yet
patients who survived the hemispherectomy died of
recurrent tumor, clinically proving the importance of the
histologic observation that tumor cells invade throughout
the brain. In the modern age, brain imaging may disclose
macroscopic tumor in the opposite hemisphere (see Figure
1) or even gliomatosis cerebri—literally a brain full of
tumor. In the years leading to up to World War II, the
German pathologist Scherer, whose scientific discoveries
were tainted by his Nazi activities, described ‘secondary
structures’ that further characterized invasive tumor cells.
These structures are ‘secondary’ because they are
dependent for their formation on underlying normal
brain structures, as opposed to ‘primary’ structures of the
tumor such as pseudopalisading necrosis and
microvascular proliferation. Examples include
perineuronal and perivascular satellitosis (accumulation of
tumor cells around neurons and blood vessels), subpial
spread, and intrafascicular tracking such as infiltration
along corpus callosum and other white matter tracks
(see Figure 2).
Advances in surgical technique, imaging, and targeting
of radiotherapy (RT) are important contributions to
local control. However, changing GBM from a disease
that kills quickly to one that can be managed as a
chronic illness,such as hypertension or diabetes mellitus,
will require systemic therapies targeting tumor cells
infiltrating throughout the brain, such as chemotherapy,
immunotherapy, and small molecule pathway inhibitors.
Present
Currently, treatment for GBM involves both local and
systemic therapy. Surgery and partial brain RT are the
standard locally directed therapies. Some physicians also
advise intra-operative placement of chemotherapy
containing polymers (i.e. Gliadel ‘wafers’) directly into
the surgical bed in an attempt to prolong local control.
While there is a modest survival benefit, the use of these
polymers remains controversial because of the potential
for toxicity. Other treatment modalities that target
disease localized to the surgical bed or the surrounding
area have included brachytherapy and stereotactic
radiosurgery (with either a linear accelerator or gamma-
knife), neither of which are commonly advised.
Convection-based chemotherapies delivered by catheter
infusion,such as local delivery of pseudomonas exotoxin
linked to either interleukin 13 (IL-13) or transforming
growth factor-? (TGF?), are available in clinical trials
for some patients. These trials take advantage of
differences in the expression of proteins (such as growth
factor receptors) on the surface of residual tumor cells in
the periphery of the operative bed to deliver the toxin
to tumor cells, but spare normal brain.
By contrast, systemic chemotherapy targets tumor cells
beyond the reach of local therapies. The most
commonly prescribed systemic chemotherapy for GBM
is temozolomide (Temodar®), an alkylator that became
available during the last decade. The effectiveness of
temozolomide in the management of GBM at diagnosis
Glioblastoma Multiforme—Past, Present, and Future
Andrew B Lassman, MD
Eric C Holland, MD, PhD
Andrew B Lassman, MD, is a neuro-
oncologist and Assistant Attending
in the Department of Neurology at
Memorial Sloan-Kettering Cancer
Center (MSKCC) in New York City. He
has experience in clinical trials for
brain tumors and works with Dr
Holland in his laboratory. Dr
Lassman’s primary focus is on
improving the understanding and
treatment of gliomas. He received
his MD and trained in neurology at
Columbia University, and he was a
neuro-oncology fellow at MSKCC
before joining the faculty.
Eric C Holland, MD, PhD, is a
neurosurgeon specializing in the
treatment of gliomas. He is an
Associate Attending in the
Departments of Neurology and
Surgery (Neurosurgery), and an
Associate Member in the Program
in Cancer Biology and Genetics at
the Sloan-Kettering Institute (SKI).
He trained in neurosurgery at
University of California Los Angeles
(UCLA), and as a post-doctoral
fellow at the National Institutes of
Health (NIH). He received his PhD
from the University of Chicago and
his MD from Stanford University.
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Brain Cancer
was recently demonstrated by a large multinational
study. A modest survival benefit of 2.5 months for
concurrent temozolomide with RT (14.6 months
median survival) was observed relative to RT alone
(12.1 months median survival). In addition, while the
survival benefit was still present two years after diagnosis,
only 10.7% of patients were progression-free and only
26.5% of patients were alive at that point.While systemic
chemotherapy improves the outcome for some patients,
long-term disease control therefore remains elusive.
Discoveries during the last several years have improved
the understanding of glioma and general cancer
biology markedly. Generally, a cancer comprises cells
that either divide or survive when they should instead
undergo either cell cycle arrest or die. These
abnormalities are also not mutually exclusive, and most
cancers, including GBMs, are driven by several
molecular abnormalities. The signal to divide is
typically provided by a growth factor (ligand).
Examples include TGF?, epidermal growth factor
(EGF), platelet-derived growth factor (PDGF), and
vascular endothelial growth factor (VEGF). Such
ligands interact with cells through receptors including
EGF receptors (EGFRs), PDGF receptors (PDGFRs),
and VEGF receptors (VEGFRs). Receptor activity is
linked with cellular processes such as mitosis or
invasion by signal transduction cascades. Examples of
signal transduction cascades important in human
GBMs include those activated by the oncogenes Ras,
Akt, and Src. In cancer cells, these pathways are
disrupted through several mechanisms. For example,
EGFR is overexpressed in up to 92% of astrocytomas,
and up to 62% of GBMs express EGFRvIII, a mutant
receptor that is active independently of ligand. Co-
expression of EGF and EGFR in GBMs leads to a
potential autocrine loop.An analogous loop is created
by PDGF and PDGFR co-expression in up to 94% of
high-grade oligodendrogliomas. Regardless of ligand
or receptor status, close to 100% of GBMs exhibit
activation of Ras, and approximately 70% exhibit
activated Akt, the latter typically through loss of the
tumor suppressor gene phosphatase tensin homolog on
chromosome ten (PTEN), which normally represses
Akt activation. Src is detected in 67% of GBMs. Finally,
control over cell division is normally maintained by
tumor suppressors, such as an inhibitor of CDK4A
(INK4A) and its alternative reading frame (ARF), as
well as p53, which also contributes to DNA repair and
apoptosis, and other enzymes. Disruptions of normal
cell cycle control of one form or another have been
observed in almost all GBMs.
Moreover, the modeling of gliomas in mice has demon-
strated that abnormalities of ligands, receptors, signal
transducers, and proliferation cause gliomas. For example,
combined activation of Ras with Akt in glial progenitors
is sufficient to induce GBMs in mice, and transgenic
expression of activated forms of Ras or Src in glia leads to
GBMs following spontaneous development of cooper-
ative oncogenic abnormalities. Modeling has also
demonstrated that PTEN loss is functionally equivalent to
Akt activation, when combined with activated Ras.
PDGF overexpression in glia causes high-grade oligoden-
drogliomas that also exhibit pathologic features of GBMs,
including pseudopalisading necrosis and microvascular
proliferation. The threshold to tumor formation is
lowered by disruption of Ink4a-Arf or p53 expression.
While more is learned about glioma biology, small
molecule inhibitors are being developed that target the
causal pathways.For example,several inhibitors of EGFRs
are under investigation in clinical trials.These include the
EGFR inhibitors erlotinib (OSI-774/Tarceva), gefitinib
(ZD-1839/Iressa), and lapatinib (GW572016). The
PDGFR inhibitors imatinib (STI-571/Gleevec) and
PTK787,both of which have other targets,are also in use.
Signal transduction cascade blockers are also being
studied. One example is R11577, which targets the
enzyme that activates Ras. Rapamycin (sirolimus), CCI-
779 (temsirolimus), and Rad-001 (everolimus) target
mTOR, one of the key enzymes activated by Akt.
Unfortunately, despite initial enthusiasm, treatment of
GBMs as well as systemic malignancies with these
small molecule inhibitors as single agents has generally
been disappointing. For example, published interim
and final reports of trials involving gefitinib, erlotinib,
Figure 1: Magnetic Resonance Imaging Findings
in Glioblastoma Multiforme
Contrast enhanced magnetic resonance image (MRI) of the brain demonstrating a large
GBM with a smaller site in the contralateral hemisphere.This infiltrative nature of GBMs,
essentially effecting the entire brain, underscores the failure of even radical surgery, such as
hemispherectomy, to effect cure.
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imatinib, PTK787, and CCI-779 monotherapy for
recurrent high-grade gliomas have not shown response
or survival rates that are markedly superior to those
observed with traditional chemotherapies, such as
temozolomide or carmustine (BCNU). However, there
are individual patients treated with these agents who
experience durable objective responses or sustained
stable disease.Therefore, these agents are likely to have
a role in GBM management.
Future
In addition to surgical resection and RT, the future of
GBM therapy is likely to involve both additional
measures to improve local control (such as convection
or catheter delivery of antitumor agents into the
operative cavity) and systemic treatment to address
infiltrative disease distant from the main tumor bed.
However, a major thrust of research will be tissue
analyses looking for molecular features that predict
sensitivity of GBMs to either traditional chemo-
therapies or small molecule inhibitors. Tailoring
therapy with specific drugs to those patients is most
likely to improve response rates and spare patients
who are unlikely to benefit the expense and potential
toxicity of these agents. Determination of a
molecularly effective dose (MED) (inhibits a
pathway), may also be more useful than the
traditionally used maximally tolerated dose (MTD).
An example of a molecular prognostic factor is loss of
heterozygosity for chromosomes 1p and 19q in
anaplastic oligodendrogliomas, which predicts both
sensitivity to chemotherapy and radiation, as well as
longer overall survival. Consequently, some neuro-
oncologists are currently using results of 1p/19q analysis
to guide therapy, although this remains an area of
controversy. Other genomic alterations are also
predictive—PTEN loss is associated with poor survival
for patients with anaplastic oligodendrogliomas and is
likely to predict poor outcome from GBM. More
recently it was reported that GBMs, in which O6-
methylguanine-DNA methyltransferase (MGMT)
expression was silenced by gene methylation, were more
sensitive to temozolomide than tumors with
unmethylated MGMT. The likely explanation is that
MGMT may counteract temozolomide activity by
removing alkyl groups on DNA. It is unclear whether
MGMT methylation impacts sensitivity of other glioma
subtypes to temozolomide, yet MGMT methylation
status may be used in the near future to guide therapy.
Individualized medicine determined by molecular rather
than simply histologic phenotype may also guide therapy
with small molecule inhibitors. Somatic mutations in
exons 18–21 of EGFR are associated with sensitivity of
lung cancer to gefitinib or erlotinib. However, the
authors and others have not found these mutations in
gliomas. Efforts are under way to identify the molecular
features that predict sensitivity of GBMs to EGFR and
other receptor tyrosine kinase (RTK) inhibitors.
Response and survival rates may also be improved
through combination therapy. For example, preliminary
data suggest that concurrent therapy with imatinib
(PDGFR/VEGFR inhibitor) and hydroxyurea (a more
traditional chemotherapy) is more effective than imatinib
monotherapy. A small series with 14 evaluable patients
with recurrent GBMs demonstrated a disease control rate
(complete response or partial response or stable disease) of
64% for patients treated with this combination. By
contrast, imatinib monotherapy led to a disease control
rate of 29%. Larger trials of this and other combinations,
such as temozolomide with PTK787, are under way.
Conclusions
Bailey and Cushing observed that gliomas become more
aggressive with time, writing “all of these lesions, so far
as our records permit us to judge, show an increasing
degree of malignancy, the recurrent tumors giving
evidence of more active cell division than the original
lesion. It is now understood that the accumulation of
molecular abnormalities underlies the increasingly
aggressive clinical behavior of an individual patient’s
glioma over time. Moreover, while GBMs may be
histologically identical, they are molecularly distinct, and
each tumor may require individually tailored treatment
with the combination of agents predicted to impact
multiple molecular abnormalities. Successful therapy of
a molecularly complex disease such as GBM may also
require simultaneous administration of multiple agents,
including both traditional chemotherapies and several
pathway inhibitors. a73
A version of this article containing references, a table and
an additional graphic can be found in the Reference Section
on the website supporting this business briefing
(www.touchbriefings.com).
Figure 2: Histology of Gliomas
(A) Pseudopalisading (arrow) necrosis (arrow head) and (B) microvascular proliferation (arrow) are the classic histologic findings in
glioblastoma multiforme (GBM). Secondary Scherer structures (C) involve tumor cells (arrow heads) accumulating around blood
vessels (BV, long arrow), and neurons (N, long arrow) in a low grade (WHO grade II) oligodendroglioma. Such perivascular and
perineuronal satellitosis, along with intrafascicular growth and subpial accumulation (not shown), contribute to the diffusely
infiltrative nature of gliomas throughout normal brain structures. Photomicrographs were kindly provided by Mark A Edgar, MD,
Department of Pathology, Memorial Sloan-Kettering Cancer Center.
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