PROCEEDINGS

CURRENT CONTROVERSIES IN THE MANAGEMENT OF HIGH GRADE GLIOMAS:

AN INTERACTIVE CASE DISCUSSION*
Alessandro Olivi,

MD,

Jaishri Blakeley, MD, and Allen K. Sills, MD, FACS

ABSTRACT
The management of glioma has evolved considerably during the last decade as significant
advances in surgery, cytotoxic chemotherapy,
targeted biological therapy, and molecular tumor
profiling have entered clinical practice. Gross
total resection (GTR) has increasingly been used
to treat patients with high-grade glioma, and
recent clinical studies have documented improved
quality of life and delayed time to glioma recurrence with this approach. Carmustine (BCNU)
wafers may be considered for the treatment of
focal tumors that are potentially treatable using
GTR and that are not situated near critical functional brain areas. Newer biopsy techniques
have made it possible to obtain tissue samples
from brain regions that were previously inaccessible. In several clinical trials of temozolomide
and radiation therapy, the DNA repair enzyme
methyltransferase
has
O6-methylguanine
emerged as an important predictor of disease
course and response to therapy. Other biomarkers that have recently been evaluated in patients
*Based on the proceedings from a symposium held during
the 2009 Joint Meeting of SNO and AANS/CNS Section on
Tumors on October 22, 2009, in New Orleans, Louisiana.
Professor of Neurosurgery and Oncology, Johns
Hopkins University School of Medicine, Baltimore,
Maryland.
Assistant Professor of Neurology, Oncology, and
Neurosurgery, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
Associate Professor, Department of Neurological
Surgery, Vanderbilt University School of Medicine,
Nashville, Tennessee.
Address correspondence to: Alessandro Olivi, MD,
Professor of Neurosurgery and Oncology, Johns Hopkins
University School of Medicine, The Johns Hopkins Hospital,
Department of Neurosurgery, Phipps Building, 1-100, 600
N. Wolfe Street, Baltimore, MD 21287.
E-mail: aolivi@jhmi.edu.

Johns Hopkins Advanced Studies in Oncology

with glioma include proteins that are important in

DNA repair and tumorigenesis, as well as newer
magnetic resonance and positron emission
tomography imaging techniques that provide
information about tumor structure and metabolism. Recent clinical trials have continued to refine
our understanding of the role of temozolomide,
radiation therapy, inhibition of angiogenesis,
and other approaches to the treatment of patients
with glioma. Although glioma remains a challenging disease with a dismal long-term prognosis, recent advances provide encouragement for
the continued development of new treatment
options for these patients.
(Adv Stud Oncol. 2010;3(1):9-23)

SURGICAL RESECTION FOR PATIENTS WITH

NEWLY DIAGNOSED OR RECURRENT GLIOMA
A growing body of recent research has changed the
way that many surgeons view the role of surgical resection for patients with newly diagnosed or recurrent
glioma. During the last decade, gross total resection
(GTR) has increasingly been selected for patients with
high- and low-grade glioma, and promising new
strategies have been developed that combine local
therapy, chemotherapy, and radiation. New surgical
techniques are also making it possible to obtain
pathology samples from patients who have traditionally been considered inoperable, and the information
provided by these techniques often has significant
implications for patient management.
GROSS TOTAL RESECTION
Surgical resection has traditionally been considered

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an option for relatively few patients with high-grade

glioma due to the poorly defined borders of these infiltrative lesions. More recently, GTR has increasingly been
used for patients with high-grade glioma. GTR was historically defined by the surgeon on the basis of operating
room observations. In contemporary clinical practice,
GTR is defined by postoperative magnetic resonance
imaging (MRI) findings, including the degree of contrast enhancement or remaining fluid-attenuated inversion recovery (FLAIR) signal abnormality.1 MRI
assessment must be performed within the first 1 to 3
days after surgery to avoid confounding the interpretation of images by postoperative inflammation and disruption of the blood-brain barrier (BBB).2,3
The role of GTR in the management of glioma is
illustrated by the MRIs shown in Figure 1, which were
obtained from 2 patients. The first patient presented
with seizures and headache, and was initially diagnosed with an unresectable tumor due to its location
within eloquent cerebral cortex. The patient underwent a successful total resection and implantation of
1,3-bis-(2-chloroethyl)-1-nitrosourea (carmustine or
BCNU) wafers with no postoperative deficit, followed
by radiation therapy and adjuvant temozolomide for 6
months. Treatment with an investigational inhibitor of
the DNA repair protein poly (ADP-ribose) polymerase
(PARP) is ongoing. The second patient presented with
seizures, dysnomia, and headache, with MRI evidence
of a lesion that involved cortical speech areas. The
patient underwent a brain biopsy and was diagnosed
with glioblastoma multiforme (GBM), which was initially classified as unresectable. GTR was performed
without any postoperative deficits and followed by
radiation therapy and temozolomide for 6 months.
After a stable disease-free and steroid-free period of
more than 16 months, the patient experienced a recurrence of GBM and underwent a second resection, with
another recurrence 3 months later.
Gross total resection also has been used successfully in patients with poorly enhancing or nonenhancing
lesions, and for patients who were initially treated with
subtotal resection but who had significant residual
impairment. Several recent reports have described significant benefits of cytoreductive surgery for patients
with gliomas who do not have substantial postoperative neurologic deficits.4-6
In addition to the potential benefits for patient
quality of life, there is also evidence to suggest that surgical resection delays the time to glioma recurrence. In

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one recent study, investigators retrospectively examined clinical outcomes for up to 12 years in patients
with low-grade glioma who underwent GTR, neartotal resection (defined as <3 mm thin residual FLAIR
signal abnormality around the rim of the resection cavity only), or subtotal resection (defined as residual
nodular FLAIR signal abnormality).4 Patients who
underwent GTR exhibited significantly longer overall
survival (P = .017) and progression-free survival
(P = .043) than patients in the other 2 groups, as well
as a trend toward greater time to conversion to highgrade glioma (P = .06). The 5-year overall survival
rates were 95%, 80%, and 70% for the GTR, neartotal resection, and subtotal resection groups, respectively. A subsequent study examined outcomes for
1200 consecutive patients with high-grade gliomas
who underwent GTR for either newly diagnosed disease or as a repeat resection.5 Patients who underwent
GTR exhibited significantly longer survival for both
primary resection and for repeat resection than
patients who underwent near-total or subtotal resec-

Figure 1. MRIs Illustrating the Role of GTR in the

Management of Glioma

A. This patient with seizures and headache underwent resection with

BCNU wafers in April 2009, followed by radiotherapy and temozolomide
for 6 months. The patient is currently receiving an investigational PARP
inhibitor.
B. This patient with seizures, dysnomia, and headache underwent a brain
biopsy and was diagnosed with GBM, which was initially classified as unresectable. GTR was performed without postoperative deficits, with radiation
therapy and temozolomide for 6 months. After a stable disease-free and
steroid-free period of more than 16 months, the patient experienced a
recurrence of GBM and underwent a second resection, with another recurrence 3 months later.
BCNU = carmustine; GBM = glioblastoma multiforme; GTR = gross total
resection; MRI = magnetic resonance imaging; PARP = protein poly (ADPribose) polymerase.
Images courtesy of Jaishri Blakeley, MD.

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tion, although the effect of GTR on survival was larger

for patients undergoing primary resection.5 Similar
observations were reported in an earlier analysis of 645
patients with high-grade GBM who were enrolled in 3
Radiation Therapy Oncology Group clinical trials.
Survival was much better for patients who underwent
total resection than biopsy alone, and was intermediate
for patients who underwent partial resection.7 Finally, a
recent study examined survival in patients with highgrade glioma as a function of Recursive Partitioning
Analysis (RPA) score, a 5-class grading system that is
based on the patients age, performance status, neurologic condition, and mental status.8 All patients were of
RPA classes III, IV, or V at baseline. The survival benefit
of complete resection was greater in patients with higher
RPA scores (ie, more severe baseline disease). The median survival for complete resection versus incomplete
resection was 17.7 months versus 12.9 months for
patients at RPA Class IV (P = .0015), and 13.7 months
versus 10.4 months for patients at RPA Class V (P =
.0398). For patients at RPA Class III, the difference
between complete resection and incomplete resection
was not statistically significant (19.3 months vs 16.3
months; P = .14). Although the extent of resection that
is required to produce a survival benefit is not well established, data from the University of California, San
Francisco Cancer Center suggest that in patients with
low-grade glioma, resection of at least 90% of the signal
abnormality is required to significantly influence survival.9 For patients with GBM, a group from MD
Anderson Cancer Center reported that resection of 98%
or more of the tumor volume was associated with
improved survival along with other prognostic factors
such as age and performance status.10
Gross total resection also has been associated with
several other benefits. Patients are likely to require less
steroid treatment, which reduces the risk of several
steroid-related adverse events, including cushingoid
habitus, steroid myopathy, peripheral edema, and
hyperglycemia. By increasing the amount of tissue
available for pathologic examination, GTR may help
to improve diagnostic accuracy. GTR also may help to
improve seizure control and make it possible to
administer local therapies (eg, BCNU wafers), and is
increasingly being required in clinical trials of new
immunotherapy regimens.
LOCAL THERAPY OF MALIGNANT GLIOMAS
BCNU-loaded wafers were approved for the treat-

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ment of newly diagnosed malignant glioma in 2003

and for recurrent GBM in 1996. Implantation of
BCNU wafers after tumor resection provides local
delivery of a high concentration of cytotoxic therapy
that is not limited by penetration of the agent
through the BBB. BCNU wafers may be considered
for the treatment of focal tumors that are potentially treatable using GTR and that are not situated near
critical functional brain areas. The use of BCNU
wafers has recently been a controversial topic among
neurosurgeons because some studies have questioned
the effectiveness of this approach.11 Central nervous
system (CNS) infection and wound infection have
been reported in some patients, with reported rates
varying from 2% to as high as 28%.12-14 Some
patients develop pronounced brain edema. In one
study, 2 of 120 treated patients exhibited acute
intracranial hypertension, which responded successfully to corticosteroid treatment in both cases.12 The
incidence of radiation-related complications is similar to the rate observed with radiation therapy
alone.15 Hence, there are side effects that may be
associated with local BCNU wafers. However, there
is substantial evidence from studies conducted in
North America and in Europe that BCNU wafers
can play an important role in the adjuvant treatment
of patients with glioma.12 These randomized phase
III studies have resulted in the US Food and Drug
Administration (FDA) approval of BCNU wafers for
both newly diagnosed high-grade malignant gliomas
and recurrent GBM. Treatment is generally well tolerated and provides an alternative approach to multimodal therapy in patients who cannot tolerate
systemic cytotoxic drugs.
As mentioned, BCNU wafers can serve as a safe
platform for multimodality therapy. The effects of
BCNU wafer implantation in combination with
radiation therapy and temozolomide were examined
in a retrospective review of 33 patients with newly
diagnosed GBM.16 The median survival was 20.7
months, with a 2-year survival rate of 36%. The
reported complications were rare and included site
infection (1 case), perioperative seizures (2 cases),
deep vein thrombosis (1 case), pulmonary embolism
(3 cases), and cerebral edema requiring urgent management (1 case). BCNU wafers are also approved for
recurrent GBM based on demonstrated improved
survival of approximately 2 months in patients with
recurrent GBM.17

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An example of the use of BCNU wafer implantation

for recurrent disease is shown in Figure 2. This patient
was a 48-year-old woman who was diagnosed with
GBM in January 2005. After her initial resection, she
received conformal radiation therapy and 12 months of
treatment with temozolomide. She experienced significant temozolomide-related systemic complications,
including Pneumocystis carinii pneumonia. In June 2006,
she was diagnosed with recurrent GBM. She underwent
resection with BCNU wafer placement and has
remained recurrence-free since that time.
Ongoing clinical research continues to define the role
of BCNU wafers in the treatment of GBM. A recent
phase I dose escalation study examined the optimal dosing of BCNU wafers, with doses from 3.8% (62 mg) to
as a high as 28% (454 mg).18 The maximum tolerated
dose was 20% BCNU by weight. Interestingly, this is
roughly 5 times the dose currently available commercially. BCNU wafers have also been evaluated as a platform
for combination therapy. For example, recent studies
have examined the addition of O6-benzylguanine (O6BG), which decreases the activity of the DNA repair
enzyme O6-methylguanine methyltransferase (MGMT)
and increases the efficacy of alkylating therapies such as
temozolomide or radiotherapy.19,20 O6-BG has been associated with unacceptable toxicity when combined with
systemic alkylating agents, but produced promising
results in a recent study in which it was administered in
combination with BCNU wafers.21

Figure 2. Example of the Use of BCNU Wafer

Implantation for Recurrent Disease

This 48-year-old woman was diagnosed with GBM in January 2005 (A). She was
treated with resection, temozolomide, and radiation. Recurrence in June 2006 is
depicted in B. She underwent second resection with BCNU wafers. In August
2009, she remained free of further recurrence (C).
BCNU = carmustine; GBM = glioblastoma multiforme.
Images courtesy of Alessandro Olivi, MD.

12

Other advances in technology are also helping to

improve outcomes in patients with GBM, including
intraoperative MRI, functional imaging, and awake
craniotomy. However, although advances in surgery
and associated technologies can help to improve outcomes, they are also associated with important potential limitations. Surgery may result in significant
vascular damage, both from removal of the tumor and
from injury to traversing blood vessels to adjacent
healthy tissue. In some cases, aggressive surgical treatment may cause ischemic events or other undesirable
outcomes that can produce significant postoperative
neurologic impairment and significantly decrease
patient survival. For example, a recent study examined
the impact of surgically acquired deficits on patient
survival in 306 consecutive patients who underwent
primary resection of GBM.22 Median survival was 12
months for patients with no new postoperative neurologic deficits, 9 months for those with new motor
deficits (P <.05), and 9.6 months for those with new
language deficits (P <.05). Thus, although aggressive
surgical resection is desirable whenever feasible, maximal precaution is required to avoid postoperative
deficits. It appears that improved surgical experience
and developing techniques are permitting more
aggressive resections without neurologic injury.
THE INOPERABLE PATIENT: THE IMPORTANCE OF
OBTAINING PATHOLOGIC CONFIRMATION OF THE
DIAGNOSIS
It is usually possible to obtain a biopsy sample even
when GBM is considered unresectable, and this sample may have a significant impact on the selection of a
treatment strategy. This is illustrated by the case shown
in Figure 3. This 58-year-old woman was previously
diagnosed with demyelinating disease, and she presented with a new episode of confusion, headache, and
vision changes. MRI revealed the large, inaccessible
lesion shown in Figure 3. She was diagnosed with
inoperable GBM and referred for hospice. The patient
and her husband sought a second opinion, and a
stereotactic biopsy revealed the lesion to be a primary
CNS lymphoma. The patient was treated with 1
course of high-dose methotrexate, which resulted in
significant shrinkage of the tumor. The lesion was no
longer visible after 3 cycles of methotrexate.
This case illustrates that the development of technologies such as a frame-based and frameless stereotactic biopsy has made it possible to obtain biopsy

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Figure 3. MRIs of a 58-Year-Old Woman Previously

Diagnosed with Demyelinating Disease

should therefore be performed when there is reasonable

assurance of protecting against neurologic deficit.
Regardless of the location of the tumor, pathology is
important in selecting an appropriate treatment. Tissue
diagnosis is required to ensure that an appropriate treatment plan is developed and applied. Newer surgical
techniques have made it possible to obtain biopsy specimens from sites that would have been considered inaccessible in the past.
THE USE OF MOLECULAR MARKERS AND BRAIN
IMAGING TO PREDICT GLIOMA COURSE AND
INDIVIDUALIZE THERAPY

These MRI images were obtained from a 58-year-old woman with confusion,
headache, and visual changes. She had previously been diagnosed with demyelinating disease and treated with a course of steroids. She was diagnosed with GBM at
another center and recommended for hospice. Biopsy revealed the lesion to be a
primary CNS lymphoma. The lesion resolved after 3 cycles of methotrexate.
CNS = central nervous system; GBM = glioblastoma multiforme; MRI = magnetic resonance imaging.
Images courtesy of Allen K. Sills, MD, FACS.

specimens from very deep brain regions that were once

considered inaccessible, including the brain stem.23 In
addition, a transfrontal contralateral approach has
been used to successfully biopsy, without significant
morbidity, deep lesions of the brain stem and avoid the
surface of the tentorium.23 Therefore, biopsy-guided
therapy should be the standard regardless of whether
the lesion is above or below the tentorium.
SUMMARY: SURGICAL RESECTION FOR GLIOMA
Recent research has prompted a significant change in
the way that surgeons view GTR for the treatment of
glioma. Historically, surgical resection was usually not
considered an option for patients with advanced disease.
More recently, several clinical studies have demonstrated
that GTR should be considered the goal of surgical treatment of glioma when feasible. Postoperative neurologic
symptoms have been associated with both diminished
quality of life and increased risk of mortality, and GTR

Johns Hopkins Advanced Studies in Oncology

Temozolomide is the foundation of therapy for most

patients with GBM. In the landmark randomized clinical trial of temozolomide given with radiation therapy
and then in the adjuvant setting versus temozolomide
alone for GBM, the median overall survival increased
from 12.1 months with radiotherapy alone to 14.6
months with the combination of radiation and temozolomide (P <.001).24 Considerable recent research has
examined several genetic, molecular, and neuroimaging
markers that may identify tumors that are especially susceptible or resistant to temozolomide therapy.
GENETIC MARKERS
A large body of recent research has focused on the
role of the DNA repair protein MGMT in modulating
the susceptibility of cells to temozolomide.
Temozolomide is an alkylating agent that targets N7 or
O6 positions of guanine residues of DNA, resulting in
interruption of cell division and subsequent cell death.
MGMT and the closely related enzyme, O6-alkylguanine-DNA alkyltransferase, repair DNA damage by
demethylating the O6 position of guanine. This
returns guanine to its baseline state and allows cell
division to continue. When the MGMT promoter is
methylated, there is decreased MGMT transcription.25
Both the amount of MGMT and the methylation status of MGMT are important determinants of the cells
ability to repair DNA. Therefore, when MGMT is
highly expressed or unmethylated, it is better able to
counter the effects of temozolomide and other forms
of alkylating therapy.26
An analysis of data from the phase III trial of temozolomide with radiation therapy versus radiation therapy
alone in patients with newly diagnosed GBM compared
treatment outcomes for patients with or without

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MGMT promoter methylation.27 Across all patients, the

suppression of MGMT by promoter methylation was a
significant predictor of treatment outcome. The median
overall survival was 18.2 months for patients with
MGMT methylation versus 12.2 months for those with
unmethylated MGMT (P <.001). The effect of adding
temozolomide to radiation therapy was larger in patients
with MGMT methylation than in those with unmethylated MGMT. In patients with MGMT promoter
methylation, the median survival was 21.7 months with
temozolomide and radiation versus 15.3 months with
radiotherapy alone (P = .007). In patients without
MGMT methylation, the median survival was 12.7
months with radiation and temozolomide versus 11.9
months for radiation alone (P = .06). Hence, MGMT
promoter methylation is prognostic of a better outcome
with radiation and temozolomide concomitant therapy.
Although MGMT expression and promoter
methylation are important prognostic factors, there are
potential limitations to the use of MGMT in treatment planning. MGMT testing is relatively complex,
and there is no clear consensus on the optimal technique to evaluate MGMT activity. The polymerase
chain reaction (PCR) procedure is widely considered
the most sensitive and specific. However, the PCR
technique requires cryopreserved tumor specimens to
provide sufficient high-quality DNA. Immunocytochemistry has also been used to assess MGMT activity. Its advantage is that it is more widely available
because it can be performed on fresh-frozen or paraffin-embedded tumor, and at lower cost. However, it
may be influenced by extraneous factors such as fixation technique or glucocorticoid treatment and hence
may be less reliable. In most recent clinical trials,
investigators have attempted to routinely obtain freshfrozen tissue that is suitable for DNA extraction in
order to allow PCR-based MGMT analysis. It is typically quite difficult to obtain and correctly freeze tissue
even in the setting of a highly structured clinical trial,
and is probably more difficult in routine clinical practice. In addition, MGMT status testing is not yet routinely paid for by health insurance plans. Patients are
therefore often required to bear the cost of this additional test (outside of the setting of a clinical trial).
Given that thus far the results of this testing do not
directly influence treatment recommendations, it is
not clear if this testing should be part of the standard
diagnostic evaluation of malignant gliomas. The correlation between test results and treatment outcome is

14

not perfect, and there is considerable variability in the

results due to factors such as the location of tissue sampled, the quality of the tissue, and how MGMT is
assayed. Finally, the most effective treatment available
currently for newly diagnosed malignant gliomas is
temozolomide and radiation therapy both for patients
with or without MGMT methylation. Until other
treatment options are available that may make the
stratification of patients based on MGMT status more
clinically meaningful, it is not clear that this test
should be performed clinically on a regular basis.
MGMT may also indirectly modulate other molecular and genetic markers that provide important
prognostic information in patients with glioma. For
example, recent in vitro studies have shown that
methylation of the MGMT promoter is associated
with overexpression of a mutant form of p53. This
mutation increases tumor invasiveness and predicts a
worse prognosis.28 Similarly, an inverse relationship
between MGMT expression and activation of the
tumor-suppressing protein phosphatase and tensin
homolog (PTEN) has been described in preclinical
models.29 In anaplastic oligodendroglioma, the most
well-defined marker is the 1p/19q chromosome
codeletion. Loss of heterozygosity at 1p and 19q is
seen in both high- and low-grade oligodendroglioma.
and predicts a better response to alkylating therapies.30,31 In vitro data and anecdotal patient observations have suggested that individuals with 1p/19q
codeletions may also have a higher percentage of
MGMT methylation.32 This may be one reason why
these patients have better outcomes with treatment.
Mutations of the isocitrate dehydrogenase genes
IDH1 and IDH2 have recently been identified as
important prognostic factors in patients with glioma.33
This relationship was first identified in a genome-wide
scan that was reported in 2008,34 in which IDH1
mutations were present in approximately 12% of all
GBMs, but were present in every patient under the age
of 30 with low-grade glioma. More recently, Yan et al
found that patients with mutations of IDH1 or IDH2
tended to have better clinical outcomes than patients
lacking these mutations.33 The protein that is encoded
by this gene has not been identified, and the physiological function of the protein as well as its interactions
with other molecular markers such as MGMT or
PTEN are unknown. It appears that patients with
IDH1 or IDH2 mutations generally do not bear mutations of other tumor-related proteins such as epider-

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mal growth factor receptor, PTEN, or cyclin-dependent protein kinase, suggesting that this marker identifies an entirely distinct subset of patients with
glioma.33 The clinical application of these mutations is
not clear at present. It is possible IDH1 or IDH2 will
help identify subtypes of patients with anaplastic
astrocytoma or secondary GBM that have a lower likelihood of progression. Research is actively ongoing to
determine the role of IDH1 and IDH2 and how they
can best be applied clinically.
IMAGING AS A PREDICTOR OF RESPONSE
Magnetic resonance imaging is essential in the
diagnosis and treatment of patients with glioma, yet it
is an imperfect tool for evaluating tissue pathology.
Gadolinium contrast is used to identify regions of
BBB disruption but does not provide information
about the specific cause of the disrupted BBB. Many
other advanced imaging techniques have been proposed to predict who will respond to various treatments and distinguish treatment-related effects from
tumor progression. Some of these techniques include
magnetic resonance spectroscopy, apparent diffusion
coefficient (ADC), amide proton transfer imaging, fluorodeoxyglucose positron emission tomography
(PET), and new PET markers including 18F-fluoroethyl-tyrosine, 18F-fluorothymidine, and 18FFDOPA.35-37 Recently, 11C-methionine has been used
with conventional MRI and gadolinium contrast
enhancement to predict treatment response to temozolomide.38 These investigators were able to use tumor
amino acid metabolism at 3 months to identify
patients with disease progression while on temozolomide. This is often very difficult to determine with
standard MRI techniques. ADC has emerged as a
potentially significant marker of treatment response in
patients who are being treated with inhibitors of
angiogenesis. ADC is routinely reported with MRI
results, and provides a measure of overall cell density.
ADC signal is low in areas where cells are densely
packed (eg, in developing tumors), whereas high ADC
levels indicate tissue necrosis.39 In one recent study,
high ADC levels predicted better response to therapy
with the anti-angiogenesis agent bevacizumab.40 A limitation of many of these imaging approaches is that
they require technology that is available to very few
research centers, are time consuming and expensive,
and they have not been validated. Nonetheless, a critical limitation in the current practice of neuro-oncolo-

Johns Hopkins Advanced Studies in Oncology

gy is the accurate interpretation of tumor response.

Hence, there are several ongoing studies to validate
these developing imaging techniques in patients
undergoing treatment for gliomas.
DISCUSSION
Q: Has there been any consideration of a clinical
trial that offers the option of giving a patient something other than temozolomide for those with
unmethylated MGMT?
Dr Blakeley: I would say that given the very good
evidence that radiation and temozolomide prolongs survival for all patients with GBM regardless of MGMT
status, I would not omit temozolomide and radiation
from first-line treatment. I would consider adding an
adjuvant therapy to temozolomide alone based on
MGMT status, and it is possible that MGMT status at
the time of recurrence would help you make decisions
about an alkylation-based therapy versus some other
strategy, such as immunotherapy. There are currently
phase III trials that are assigning patients with newly
diagnosed GBM to the experimental treatment arm
based on MGMT status. However, the lack of alternative
therapies that show promise of efficacy in the setting of
unmethylated MGMT has limited this approach. It
would be very reasonable to focus therapies for methylated versus unmethylated patients once we have additional treatment options.
Q: We describe MGMT as methylated or unmethylated. But within a particular patient, is MGMT
methylation consistent across an entire tumor? Or
does it vary from region to region?
Dr Sills: One study that examined this found a
fairly homogeneous distribution of MGMT methylation within multiple sample points within high-grade
gliomas.41
Dr Blakeley: A paper that was published in 2008
found the opposite.42 When they serially sampled
patients at the time of original diagnosis and then at the
time of recurrence, they found that the MGMT status
was not reproducible by the same means. In another
study, patients could exhibit different MGMT status
depending on where the sample was taken.43 These
results highlight that the techniques used to assess
MGMT and MGMT methylation versus expression
may significantly influence results and make it difficult
to rely on MGMT as a prognostic marker in patients
with newly diagnosed malignant gliomas.

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Dr Olivi: I would also think time is going to play

a factor. An enzyme is not at a constant level all of the
time. There are going to be variations depending on
the time of sampling, other pretreatment factors, history of steroids, and other agents that have been used
in the patients treatment.
SUMMARY: BIOMARKERS IN THE MANAGEMENT OF GLIOMA
Many potential genetic, molecular, and neuroimaging markers of prognosis or treatment response
have been evaluated in patients with malignant
gliomas. The DNA repair enzyme MGMT has consistently been shown to significantly influence disease
course and the response to temozolomide and radiation therapy. MGMT also interacts with other tumorrelated proteins that might serve as prognostic or
predictive biomarkers. MRI techniques and nuclear
medicine approaches are providing new methods to
image physiological responses in addition to the
anatomical changes standard imaging provides.
EMERGING EVIDENCE FOR THE TREATMENT
PATIENTS WITH MALIGNANT GLIOMA

OF

For patients with glioma, some treatment strategies

are known to be effective and are supported by evidence from well-designed clinical trials, whereas other
potential approaches remain investigational or speculative. As described earlier, maximal feasible resection
is an important goal for patients with malignant glioma,
and radiation with concurrent temozolomide is the current standard of care for patients with newly diagnosed
GBM. This combination is also used in patients with
anaplastic astrocytoma, although no clinical trials have
clearly demonstrated the effectiveness of this strategy. It
is even less clear whether this combination is appropriate for patients with anaplastic oligodendroglioma, particularly those with 1p19q codeletion. Several phase III
studies will open this year to address these questions.
Other commonly used therapies for GBM include
BCNU wafers and recently, bevacizumab. BCNU
wafers are FDA approved for recurrent GBM and can
serve as an excellent platform for multimodality therapy
in these patients. Bevacizumab monotherapy was
recently approved by the FDA for recurrent GBM.
Since its approval, bevacizumab has been widely used at
the time of first recurrence for patients with GBM,
although there are several limitations associated with
bevacizumab that should be considered in a multispe-

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cialty setting to set forth the most rational strategy for

each individual patient.
TEMOZOLOMIDE AND RADIATION THERAPY
As described previously, the role of temozolomide
in GBM is supported by the results of a large clinical
trial that was initially reported in 2005 in the New
England Journal of Medicine, in which the addition of
temozolomide to radiotherapy was superior to radiotherapy alone in patients with newly diagnosed
GBM.24 A recent report of 5-year outcomes from this
study demonstrated significant long-term benefits of
temozolomide and radiation versus radiation alone
regardless of patient age, extent of resection, or
MGMT methylation status.44 Overall survival after 5
years was 9.8% with temozolomide and radiotherapy
versus 1.9% with radiotherapy alone (P <.0001).
Although this survival rate is low, it represents a significant advance over previously available treatment
strategies, and suggests that future efforts building on
this initial success may provide even larger survival
benefits. Although all patients benefited from temozolomide added to radiation therapy, the long-term
report from this study showed that MGMT status was
the single most predictive factor of a favorable
response to temozolomide treatment.
The most common risks of combination therapy
with temozolomide and radiation included hematologic adverse events such as thrombocytopenia and
leukopenia. In a retrospective evaluation of hematologic toxicity associated with temozolomide and radiotherapy at a single institution, approximately 20% of
patients experienced grade 3 to 4 thrombocytopenia,
and 10% required platelet transfusions. The median
duration of severe thrombocytopenia requiring transfusion was approximately 1 month, and 4% were
transfusion dependent for 6 months or longer.45
Perhaps more importantly, 17% of patients in this
study discontinued treatment due to thrombocytopenia. Discontinuation of treatment is especially significant for these patients because there are very few other
options for tumor treatment if their hematologic function does not improve.
Changes in CD4+ cell count have also been
increasingly recognized as an important factor in
patients treated with temozolomide and radiation. All
patients who are treated with this combination therapy exhibit some decline in CD4+ count, although the
extent of this decrease varies from patient to patient.

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Unpublished observations suggest that nearly all

patients will experience a decline to less than
200/mm3 early in the course of combination therapy.
This marks a profound loss of immune function that
is similar to the definition of AIDS onset in patients
with HIV infection.46,47 More importantly, the decline
in CD4+ count appears to be sustained over time, and
may be associated with decreased survival. However, it
is unclear whether low CD4+ levels should lead to discontinuation of temozolomide, and if so, what the
threshold CD4+ count for discontinuation should be.
OTHER CLINICAL CONSIDERATIONS
IN GLIOMA MANAGEMENT
Several other factors must also be considered in
managing patients with glioma. Hyperglycemia is a
common and potentially serious complication of
glioma treatment. In a recent study, uncontrolled
hyperglycemia (which was defined as blood glucose
concentration >137 mg/dL) was associated with a
lower survival rate in patients with glioma, even after
controlling for steroid use, degree of resection, age,
and performance status.48 Patient mobility is often
impaired as a result of steroid-induced myopathy,
especially for patients who require high steroid doses
for long periods of time. Patients should be questioned
about difficulty using stairs or when moving from a
sitting to a standing position. Physical therapy is often
helpful for patients with cancer who have significant
mobility problems. Timely diagnosis and treatment of
infection is essential, especially in consideration of the
low CD4+ cell counts that are common among patients
with glioma. Finally, seizure management is important
to help maintain quality of life. Newer antiepileptic
agents such as levetiracetam, zonisamide, and topiramate
are often very effective and well tolerated, and are unlikely to interact with chemotherapy agents.
The term pseudoprogression has been used to
describe a pattern of radiographic evidence of glioma
progression immediately following treatment that is
actually due to other causes, such as treatment-related
inflammation, ischemia, infection, or seizures.49
Pseudoprogression occurs in as many as 20% of
patients treated with temozolomide and radiation, and
may account for as much as 50% of the post-treatment
MRI change in these patients.49,50 For this reason, most
clinical trials now require that patients continue MRI
assessments for at least 3 months after the completion
of treatment to ensure that progression is due to GBM

Johns Hopkins Advanced Studies in Oncology

rather than pseudoprogression. Although the identification of the underlying cause of pseudoprogression is
clearly important in selecting an appropriate management strategy, it can be difficult to distinguish among
the various potential causes of imaging changes using
conventional imaging techniques. Clinical signs and
symptoms (eg, worsening seizures or headaches) also
do not reliably distinguish true progression from treatment-related MRI changes. For this reason, a great
deal of work is ongoing to identify new imaging
modalities that may better distinguish between tumor
progression and pseudoprogression.
TEMOZOLOMIDE AND RADIATION FOR
OTHER HIGH-GRADE GLIOMAS
The use of temozolomide and radiation therapy for
other high-grade gliomas is illustrated by the patient
shown in Figure 4. This 64-year-old woman presented
with seizures, and MRI revealed the left temporal lobe
brain lesion shown in Figure 4. She was treated with
antiepileptic drugs and was stable with no new seizure
episodes for 4 years. Four years after the beginning of
treatment, a follow-up MRI revealed progression of
the lesion. Because she was over 40 years old and had
a large infiltrative high-grade glioma, she was not considered a candidate for complete resection. She underwent partial resection, and on the basis of tumor

Figure 4. Use of Temozolomide and Radiation

Therapy for Other High-Grade Gliomas

This 64-year-old woman with seizures had a left temporal brain lesion. She
was treated with antiepileptic drugs, and imaging was stable for 4 years. She
then exhibited imaging progression and underwent partial resection.
Pathology revealed anaplastic astrocytoma. Note the nonenhancing infiltrative lesion in the medial left temporal lobe.
Images courtesy of Allen K. Sills, MD, FACS.

17

PROCEEDINGS

pathology was diagnosed with anaplastic astrocytoma.

She began treatment with temozolomide and radiation
therapy. At day 21 of combined therapy her platelet
count decreased to 38 000 cells/L; after 30 days, her
white blood cell count was 90 cells/L and her
absolute neutrophil count was 0. She was hospitalized
with neutropenic fever and began receiving platelet
transfusions. She also was treated with antibiotic and
antifungal therapy. After aggressive management of
her infectious complications, she ultimately was able
to be discharged to home. However, her platelet and
white blood cell count never recovered to normal and
she was not a candidate for systemic therapies when
her tumor progressed several months later. Options
were presented to the patient and her family; however,
due to her poor functional status, they opted for supportive care alone.
Patients with anaplastic oligodendroglioma as
defined as those with 1p19q codeletion are more likely to respond to any form of therapy (radiation therapy or alkylating chemotherapies).51 However, there is
concern that radiation and temozolomide in these
patients may increase the risk for brain injury, and
there is no consensus about what therapy is optimal
for newly diagnosed anaplastic oligodendroglioma
with 1p19q codeletion. Ongoing clinical trials are
examining several treatment scenarios, including radiation and temozolomide for anaplastic oligodendroglioma with or without 1p/19q, for low-grade
glioma, and for anaplastic astrocytoma. This issue is of
considerable clinical importance because clinical trials
are increasingly examining agents that affect DNA
repair enzymes in combination with other treatment
strategies. For example, ongoing clinical trials of
patients with MGMT methylation are examining
PARP inhibition in combination with radiation and
temozolomide. It is not know whether studies such as
these pose a significant risk of CNS injury to the participants. Finally, it is not clear whether there are
patient subgroups that are especially likely to benefit
from temozolomide and radiation therapy.
THE EMERGING ROLE OF ANGIOGENESIS INHIBITORS
IN THE TREATMENT OF GLIOMA
Treatments that target angiogenesis have been
shown to produce several clinically significant effects
in patients with glioma, including increased progression-free survival in patients with recurrent GBM,
reduced dependency on steroids, and reduction of

18

intracranial pressure for some patients.52 Published

response rates have varied from approximately 20% to
57%,53,54 with lower rates in studies that used blinded
central review. Even the lowest reported response rates
compare favorably with published response rates of 8%
to 10% in clinical trials of other treatment strategies for
GBM. However, angiogenesis inhibition has not been
shown to significantly improve overall survival. It
should also be noted that progression in clinical trials is
measured using gadolinium enhancement on MRI. It is
therefore possible that the reported effects of anti-angiogenesis therapy actually reflect an effect on the BBB,
rather than a specific antitumor effect.
There are also several potential limitations of antiangiogenesis therapy. Inhibition of angiogenesis may
change the natural history of GBM. For example, in
an animal xenograft model study, tumors that were
exposed to bevacizumab gained features of increased
tumor invasiveness and migration.55 It is not clear to
what extent this occurs in patients. It also has been
suggested that inhibition of angiogenesis may cause a
state of brain addiction, and that the withdrawal of
bevacizumab in a responsive tumor may result in rapid
tumor expansion.56 Recent data suggest that bevacizumab withdrawal probably does not promote
explosive tumor growth, but that it may simply allow
a tumor that has been progressing without mass effect
due to edema and disrupted vasculature to become
clinically apparent and symptomatic. Bevacizumab is
also relatively expensive and has thus far not been
shown to improve overall survival in patients with
glioma. Bevacizumab is generally well tolerated and
has side effects that do not overlap with the cytotoxic
therapies it is often paired with. However, bevacizumab is associated with infrequent but potentially devastating adverse events, such as gastrointestinal
perforation, intracranial hemorrhage, and thrombotic
events (eg, deep vein thrombosis and pulmonary
embolism).57,58 Several recent clinical trials have
demonstrated that bevacizumab produces objective
treatment responses in many patients with glioma. An
open-label, multicenter, randomized phase II clinical
trial examined bevacizumab as single-agent therapy or
in combination with irinotecan in previously treated
patients with GBM.59 Treatment response was examined using a blinded central review, and patients who
progressed on bevacizumab alone were crossed over to
combination therapy. Response to bevacizumab was
noted for 28.2% of patients for bevacizumab alone

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versus 37.8% for bevacizumab plus irinotecan. The 6month progression-free survival was 42.6% for bevacizumab alone and 50.3% for combination therapy.
Adverse events included infection, fatigue, hypertension, headache, hemorrhage, and thrombosis. Patients
on bevacizumab alone were less likely to have grade 3
or greater adverse events (46.4%) than patients treated
with bevacizumab and irinotecan together (65.8%). A
similar trial at the National Cancer Institute showed
an objective response rate of 19.6% with a median
duration of response of 3.9 months.60 Based on these
reports, the FDA granted accelerated approval for single-agent bevacizumab for patients with progressive
GBM. As a result of this approval, bevacizumab has
been widely used in patients with recurrent or progressive malignant gliomas. However, some concerning trends are arising. For example, thus far there is no
therapy identified to effectively control the tumor after
progression on bevacizumab.61 Moreover, both clinical
reports and preclinical reports raise the possibility that
bevacizumab may possibly change the behavior of
some tumors, perhaps actually increasing the propensity for infiltration.55,62,63
Subsequent clinical trials have examined the efficacy of bevacizumab administration in patients with
early or late glioma. In a pilot study, 10 patients with
newly diagnosed GBM were treated with bevacizumab
in combination with temozolomide and radiation
therapy.64 Bevacizumab was administered at a dose of
10 mg/kg every 2 weeks, beginning of the first day of
temozolomide and radiation therapy. The toxicity of
this approach was generally acceptable. Adverse effects
included presumed radiation-induced optic neuropathy, fatigue, myelotoxicity, wound breakdown, deep
vein thrombosis, and pulmonary embolism. A larger
phase II clinical trial to examine the efficacy and tolerability of bevacizumab for early GBM is in progress.
Several other ongoing phase II and phase III trials are
examining various bevacizumab strategies in early disease, including bevacizumab after radiation therapy
and temozolomide, bevacizumab and erlotinib after
radiation and temozolomide, and bevacizumab in
combination with irinotecan.
Another recent phase II clinical trial examined the
addition of bevacizumab to repeat radiation for
patients with recurrent disease.65 Repeat radiation is
often difficult for patients to tolerate and can result in
extensive edema and the need for high steroid doses.
In patients with focal lesions smaller than 3 cm, repeat

Johns Hopkins Advanced Studies in Oncology

radiation with bevacizumab produced an overall

response rate of 50%, a 6-month progression-free survival rate of 65%, median overall survival of 12.5
months, and 1-year survival of 54%. Toxicities included intratumoral hemorrhage, wound dehiscence, and
bowel perforation.
Use of bevacizumab in patients with GBM requires
the consideration of several logistical issues.
Anticoagulation is important because many patients
with high-grade gliomas develop deep vein thrombosis. One recent study found that anticoagulation could
be safely administered in patients receiving bevacizumab without increasing the risk of hemorrhage.66
A pre-existing symptomatic intracranial hemorrhage is
an absolute contraindication to bevacizumab, and
bevacizumab must be discontinued if symptomatic
intracranial hemorrhage develops during therapy.
However, for patients with evidence of a prior hemorrhage on MRI (eg, bleeding from a prior surgery), a
recent retrospective study of 27 patients with recurrent
malignant glioma found that it is reasonable to continue bevacizumab.67 Of 12 patients who had radiographic evidence of intracranial hemorrhage before
treatment, only 1 patient required termination of therapy due to symptomatic progression of hemorrhage.
Some of the issues relating to bevacizumab therapy
for patients with glioma are highlighted by the patient
described in Figure 5. This 52-year-old man presented
with aphasia and a seizure. MRI revealed the left posterior frontal lesion shown in Figure 5A. He underwent GTR followed by 3 cycles of radiotherapy and
temozolomide. MRI revealed continued disease progression, and he was started on bevacizumab and
irinotecan, which produced marked improvement in a
follow-up MRI. After another 5 months, he began to
develop progressive aphasia and hemiparesis, and his
steroid requirement increased. He returned to surgery
for debulking, which revealed extensive necrotic tissue.
After surgery his speech improved but his motor function worsened. An MRI 3 months after his second
surgery revealed improvement, but his function continued to decline. He elected to enter hospice, and
died 2 months later. This case demonstrates that the
use of bevacizumab may complicate the issue of when
to perform surgery, and whether the safety of surgical
therapy is changed by bevacizumab use. This case also
points out that it is possible for the patients symptoms
and MRI findings to diverge over time, with the scan
improving but symptoms worsening.

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Figure 5. Issues Relating to Bevacizumab Therapy

for Patients with Glioma

A. This patient was a 52-year-old male with aphasia and a seizure. B. This
image was obtained after radiation therapy and temozolomide followed by
3 cycles of adjuvant temozolomide. C. This image was obtained after 5
months total on bevacizumab. At this time, the patient exhibited progressive aphasia, hemiparesis, and increasing steroid requirement. D. MRI was
performed again 3 months after his second surgery. He was still on bevacizumab, but now exhibited increasing steroid requirement and worsening
speech function. He opted for hospice care and died 2 months later.
MRI = magnetic resonance imaging.
Images courtesy of Allen K. Sills, MD, FACS.

DISCUSSION
Q: Is hyperglycemia something we can control? Or
is it a function of the illness?
Dr Blakeley: I make robust efforts to control
hyperglycemia. Of course there is a risk to that. If you
overshoot then someone is hypoglycemic. So we have
to be careful about how we manage it. I work closely
with my referring physicians, primary care physicians,
family practice doctors, and a diabetes clinic. It is very
similar to the way in which we use an anticoagulation
clinic for international normalized ratio.
Q: It has been suggested that MGMT methylation
may indicate an increased likelihood of pseudoprogression. Is that useful?
Dr Blakeley: In a paper published last year,
there was an association between pseudoprogression

20

and MGMT status.68 The problem still remains of

how to best assay it and what to say about what portion of the tumor or surrounding tissue was sampled. In many of these cases, the investigators have
looked at the initial tumor at the time that the
patient had the first resection, which might not be
predictive of what is happening at the time of recurrence. That said, MGMT status may be an extra
helpful piece of information to use when trying to
assess if there is actual tumor progression versus
pseudoprogression.
Dr Olivi: I think that probably this might be one
expression of a particular individual predisposition to
an increased susceptibility and subsequent development of pronounced treatment effects. I believe that
one of the areas in which we can make progress in a
relatively short period of time is the identification of
patients who will be more prone to certain negative
treatment reactions. There is an individual and nonuniform response to certain treatments that probably
could be identified beforehand.
Dr Sills: I am much more likely to deem it
pseudoprogression if there is a lack of new clinical
symptoms. So my standard response would be if I
have got a scan that looks progressive and I am concerned about pseudoprogression, if the patient is
asymptomatic then I will usually opt for observation alone with shortening of the interval imaging
period. Instead of waiting 8 weeks, I might bring
them back in 4 weeks for another image. I have
rarely seen a patient with true progression who
remains asymptomatic for any great length of time.
Thus the longer the patient goes without any new
symptoms, the more I am inclined to believe it is
pseudoprogression.
Q: In the last case you described, the patients MRI
appeared to improve while his symptoms worsened.
What would you expect to see on FLAIR imaging
in a case such as this?
Dr Sills: The patients FLAIR imaging also
improved at the time the patient was clinically deteriorating.
Dr Blakeley: That is a good point, because many
times you will see the contrast enhancement getting
better and better while the FLAIR and the diffusion
will actually get worse. Sometimes that is interpreted
as ischemia, but it might be caused by the concentration of cells, as we would expect with ADC.

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Q: Could you comment on P carinii pneumonia

prophylaxis?
Dr Blakeley: We use sulfamethoxazole and
trimethoprim, which is administered Monday,
Wednesday, and Friday at double strength and continued for the duration of therapy or until the CD4 count
goes above 200. I measure CD4 count before therapy, 1
month after radiation and temozolomide, and monthly
thereafter until I see it go above 200, and continue sulfamethoxazole and trimethoprim unless they have an
adverse event. In that case, we would substitute something else, such as diaminodiphenyl sulfone.
Q: What is the pharmacokinetic profile of bevacizumab? When does it disappear from the system?
Dr Blakeley: Between 3 and 4 weeks.
SUMMARY: EMERGING EVIDENCE FOR
THE TREATMENT OF MALIGNANT GLIOMA
During the last decade, progress in surgical techniques and chemotherapy has significantly improved
the management of patients with glioma, with higher
rates of durable response and better management of
adverse treatment effects. Research has continued to
highlight the importance of individualizing therapy
and for the patients specific clinical features and overcoming practical obstacles to treatment, such as treatment-related leukopenia. Anti-angiogenesis therapy
has emerged as an important option for many patients
with glioma, although there are significant limitations
and the optimal timing for initiating these agents is
not known. A multidisciplinary approach is essential
for planning and coordinating surgical care,
chemotherapy, radiation therapy, and supportive care,
and for evaluating and interpreting the response to
treatment. Management of treatment and diseaserelated complications may have as great an impact on
survival and quality of life as therapeutics and need
careful attention. Recent advances in glioma therapy
provide encouragement for the continued development of new treatment options for these patients.

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Johns Hopkins Advanced Studies in Oncology

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