2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ESTABLISHING TREATMENTS FOR GLIOBLASTOMA
Fig. 1. Treatment schema for the chemoradiation regimen
from the EORTC/NCI-Canada Clinical Trial.
of 9.8% in the combined treatment patients compared with
1.9% in the radiation-only group. 12
A companion laboratory correlative study to the EORTC/
NCIC trial evaluating patient outcomes on the basis of the
methylation status of the methylguanine methyltransferase
(MGMT) gene was performed by Hegi and colleagues. 8
Hypermethylation of the promoter region was postulated to
decrease or eliminate gene expression and that with absent
or low intracellular MGMT, a major mechanism of repair of
alkylating agent–mediated DNA damage. Therefore, in the
presence of the methylated MGMT promoter region, the
addition of temozolomide would result in a better response
rate. They were able to analyze 206 and found that 45% were
had MGMT promoter methylation. These studies did demonstrate
an improved outcome for patients with tumors
harboring methylated MGMT gene promoter regions. However,
although not as marked, the outcomes for patients
with unmethylated tumors experienced improvement with
the addition of temozolomide, suggesting that MGMT methylation
status is clearly prognostic but not fully predictive of
treatment benefit.
These findings, correlating MGMT promoter methylation
with outcomes, suggested that the MGMT enzyme may be
an important therapeutic target and depletion of intracellular
MGMT in tumor cells may enhance temozolomide
efficacy. Prolonged exposure to temozolomide has been demonstrated
to decrease MGMT activity in peripheral-blood
mononuclear cells in patients receiving 21 consecutive days
of treatment. 13 This approach, using a dose-dense treatment
schedule, was tested in Radiation Therapy Oncology Group
KEY POINTS
● A standard of care consisting of concurrent radiation
and temozolomide followed by adjuvant temozolomide
has been established for patients with newly
diagnosed glioblastoma.
● Recently completed and ongoing randomized clinical
trials in newly diagnosed glioblastoma seek to enhance
the current therapy by adding synergistic
therapies.
● There are very few treatments established for recurrent
glioblastoma despite extensive testing of many
signal transduction modulators.
● Antiangiogenic therapies look promising for recurrent
glioblastoma. Bevacizumab is administered frequently
in this setting.
● Given the molecular heterogeneity of glioblastoma,
further advances will likely require a comprehensive
effort merging tumor profiling with targeted
therapies.
(RTOG) 0525, an international collaborative phase III
trial. 14 Enrollment criteria included adults older than 18
years with available tumor tissue blocks with more than
1cm 2 of tumor and Karnofsky performance score of 70 or
greater. All patients received concurrent radiation with
daily temozolomide and then were randomly assigned to
either standard adjuvant temozolomide (150 to 200 mg/m 2 /
day for 5 consecutive days of a 28-day cycle) or dose-dense
temozolomide (75 to 100 mg/m 2 /day for 21 consecutive days
of a 28-day cycle). Patients could receive treatment for up
to 12 cycles of adjuvant therapy. The study accrued 1,173
patients with 833 undergoing random assignment. The two
treatment arms were well balanced in all parameters including
age, gender, performance status, extent of tumor resection
and MGMT methylation status. The results, presented
at the 47 th ASCO Annual Meeting (June 4–8, 2011, Chicago,
IL), demonstrated that there was no improvement in either
overall or progression-free survival with the use of the
dose-dense temozolomide schedule. Additionally, subset
analysis by MGMT methylation status did not show a
selective benefit for dose-dense treatment for tumors with
either methylated or unmethylated MGMT gene promoter
phenotype. However, this prospective study did demonstrate
that MGMT methylation status is clearly prognostic.
Other strategies have been evaluated as potential enhancers
of the established efficacy of the chemoradiation regimen.
A series of signal transduction modulators and other
similar agents have been evaluated, typically in single-arm
phase II trials. Agents such as erlotinib, talampanel, and
Poly ICLC have been tested with promising results compared
with the historic controls provided by the EORTC
study. 15,16 However, the validity of this comparison has been
questioned, and concerns regarding patient population differences
and the more recent availability of effective salvage
regimens have limited interest in pursuing large-scale clinical
trials.
Interest in the use of antiangiogenic strategies has generated
several large-scale randomized clinical trials. Bevacizumab,
a humanized monoclonal antibody targeting
vascular endothelial growth factor (VEGF) A, has demonstrated
activity in patients with recurrent glioblastoma
(discussed in more detail later herein). This has led to the
development and completion of two randomized, doubleblind
placebo-controlled trials for patients with newly diagnosed
glioblastoma. The results of the two studies (RTOG
0825 and AvaGLIA) are expected within the next 2 years.
Additionally, data from a phase II trial adding the integrin
inhibitor cilengitide to the conventional chemoradiation regimen
showed an improved outcome in newly diagnosed,
MGMT-methylated glioblastoma compared with historic
controls and led to a phase III placebo-controlled randomized
trial. 17 This study recently completed accrual and
outcome results are expected soon. Other studies including
randomized phase II trials evaluating mammalian target
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