2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Future Directions in Glioblastoma Therapy
Overview: The standard of care for both newly diagnosed and
recurrent glioblastoma (GBM) patients has changed significantly
in the past 10 years. Surgery followed by radiation and
concurrent and adjuvant temozolomide is now the wellestablished
standard treatment for newly diagnosed GBM.
More recently, bevacizumab has become a mainstay of treatment
for recurrent GBM. However, despite these advances and
significant improvements in patient outcomes, the management
and treatment of GBM patients remains a challenging
and frustrating endeavor. Difficulties in interpretation of imaging
changes after initial treatment, as well as the effects of
antiangiogenic agents like bevacizumab on MRI characteristics,
can make even the determination of disease progression
complicated in multiple situations. Although a high percentage
of patients benefit from antiangiogenic therapy in terms
of radiographic response and progression-free survival, the
GLIOBLASTOMA (GBM) IS the most common malignant
brain tumor in adults, with approximately 15,000
new GBM cases diagnosed each year in the United States.
GBM is classified by the World Health Organization (WHO)
as a grade 4 astrocytic tumor and is differentiated from
lower grade astrocytomas by the pathologic features of
pseudopalisading necrosis and microvascular proliferation,
among others.
Standard Therapy for Newly Diagnosed GBM
Radiographically, these tumors typically present as ring
enhancing masses on contrast-enhance MRI imaging, often
associated with marked infiltration and edema of surrounding
brain. Standard treatment for newly diagnosed GBM
includes maximal safe resection followed by chemoradiation,
as defined by the phase III study by Stupp and colleagues. 1
This standard treatment includes fractionated external
beam radiation given over 6 weeks to a dose of 60 Gy
combined with daily temozolomide at a dose of 75 mg/m 2 .
This initial concurrent chemoradiation phase is followed by
adjuvant temozolomide treatment at a dose of 150 mg/m 2
day 1 through 5 out of 28 for the first cycle, with dose
escalation to 200 mg/m 2 day 1 through 5 out of 28 for
subsequent cycles. The duration of adjuvant therapy in the
initial study was 6 months, but subsequent studies have
continued adjuvant treatment out to 12 months or more.
Although this regimen demonstrated significant improvement
in median survival compared with radiation alone
(14.6 months compared with 12.1 months, p � 0.001) and a
benefit in 2-year survival rates (26.5% compared with
10.4%), long-term survival for GBM patients remains disappointing.
In a follow-up analysis of the initial phase III
study, 2-, 3-, and 5-year survival rates were 27.2%, 16.0%,
and 9.8%, respectively in the temozolomide chemoradiation
group. 2 More recently, a phase III study comparing two dose
schedules of adjuvant temozolomide after chemoradiation
(RTOG 0525) was reported with no significant difference in
overall survival between the standard and dose-dense temozolomide
groups. 3 Together, these studies demonstrate that
temozolomide chemoradiation has a significant benefit in
newly diagnosed GBM compared to radiation alone (and
prior chemotherapy/radiation combinations). However, de-
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By Howard Colman, MD, PhD
effects of bevacizumab on prolonging overall survival remain
controversial. Furthermore, tumor progression after treatment
with antiangiogenic agents carries a particularly poor prognosis
and there is a general lack of effective therapies for this
group of patients. These limitations in terms of standard
treatments contrast with a relative wealth of new information
regarding the molecular underpinnings of GBM. Data from
several large-scale efforts to molecularly profile GBM tumors
including The Cancer Genome Atlas (TCGA) project have
helped define specific molecular subtypes of GBM with distinct
biology and clinical outcomes. These findings are helping
to refine our understanding of the molecular heterogeneity
and pathogenesis of these tumors and provide a basis for the
future development of rational and targeted therapies for
specific tumor subtypes.
spite this improved standard of care, the majority of patients
still die of their disease before 2 years.
The Problem of Pseudoprogression
One aspect of the management of GBM patients that
causes significant uncertainty is the issue of interpretation
of MRI imaging and disease progression. Gadoliniumenhanced
MRI remains the mainstay of assessment of GBM
status. However, changes in enhancement on MRI reflect
changes in vascular permeability, and are thus an imaging
surrogate for disease status rather than a reflection of true
tumor burden. Other causes of increased vascular permeability
can increase the extent and degree of enhancement on
MRI, resulting in a potentially incorrect determination of
tumor progression. This need to differentiate “pseudoprogression”
(a radiographic increase in MRI enhancement or
edema resulting from tissue injury or inflammation without
increased tumor activity) from true tumor progression represents
a clinical and diagnostic challenge, particularly in
patients who have recently completed radiation with concurrent
chemotherapy. 4 Pseudoprogression typically stabilizes
or improves without alteration in treatment within 3 to 6
months. Pseudoprogression rates have been reported between
9% and 31% in patients with malignant glioma after
chemoradiation, with significantly higher incidence in tumors
with MGMT promoter methylation. 5,6
Since conventional MRI often cannot distinguish true
progression from pseudoprogression, a lot of attention has
been focused on other advanced imaging modalities. Although
MRI perfusion, MRI spectroscopy, and PET can add
diagnostic information and aid in clinical decision making,
none of these are sufficiently sensitive or specific to definitively
determine the underlying etiology. 7 An incorrect determination
of progression in these patients can lead to
From the Department of Neurosurgery and Huntsman Cancer Institute, University of
Utah, Salt Lake City, UT.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Howard Colman, MD, PhD, 175 North Medical Drive East,
Salt Lake City, UT, 84132; email: howard.colman@hci.utah.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10