2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

FUTURE DIRECTIONS IN GBM THERAPY
premature discontinuation of an effective therapy and/or
initiation of less effective therapies. In addition, treatment
of pseudoprogression as progression with an alteration in
therapy can lead to a misinterpretation of subsequent imaging
improvement as a “response” to the new therapy. For
these reasons, a clear understanding regarding the issues
and limitations of current imaging is crucial for clinicians
managing these patients. To help guide these decisions, the
recent recommendations by the Response Assessment in
Neuro-Oncology (RANO) Working Group are that progression
can only be determined with certainty in the 12 weeks
after initial chemoradiation by pathologic confirmation or if
the majority of the new enhancement is outside the original
high-dose radiation field. 8 Patients in which the determination
of progression cannot be made with certainty should not
be enrolled in clinical trials during this time period, and
patients who remain clinically stable or in whom pseudoprogression
is suspected should continue with their current
therapy.
Standard Therapies for Recurrent GBM
Following disease progression, historic outcomes for treatment
of recurrent disease have been disappointing. In
pooled analyses of multiple clinical trials for recurrent
GBM, response rates have ranged from 4% to 7%; 6-month
KEY POINTS
● Radiation therapy with concurrent temozolomide and
adjuvant temozolomide is the established standard
treatment for newly diagnosed glioblastoma (GBM).
● Pseudoprogression is an important complicating factor
in the interpretation of MRI imaging of GBM
patients and practitioners need to have a good awareness
of this issue and familiarity with current recommendations
by the Response Assessment in Neuro-
Oncology (RANO) Working Group.
● Although multiple therapeutic options exist for recurrent
GBM, bevacizumab monotherapy remains the
most common standard salvage therapy. However,
bevacizumab treatment is associated with modest
effects on overall survival, difficulties in imaging
interpretation of progression, and the development of
resistance and poor prognosis at progression.
● Understanding of the molecular alterations associated
with distinct molecular subtypes and clinical
outcome in GBM continues to increase. Key biomarkers
with prognostic and/or tumor subtype associations
include proneural and mesenchymal gene
expression patterns, MGMT promoter methylation,
IDH1 mutation, and CpG island methylation phenotype
(CIMP).
● The efficacy and evaluation of targeted therapy in
GBM can be complicated by issues of drug permeability
and difficulty in assessing biologic endpoints in
the tumor, and these aspects have to be addressed in
current and future clinical trials to increase the
likelihood of further improvements in outcome.
progression-free survival (PFS) rates ranged from 9% to
15%; and median overall survival (OS) rates ranged from
5–7 months. 9,10 Standard treatment options for recurrent
disease are more varied than for newly diagnosed patients,
with recent United States Food and Drug Administration
(FDA) approvals adding to the number and types of standard
treatment options. Reresection alone or with placement
of polifeprosan 20 with carmustine is an option for patients
with recurrence in noneloquent areas of the brain. 11,12
Treatment with additional cytotoxic chemotherapy is frequently
considered, with several potential choices. Retreatment
with alternative schedules of temozolomide has some
efficacy, with one study suggesting improved 6-month PFS
and one-year survival in patients who had been stable for
at least several months after completing standard adjuvant
temozolomide, but with poorer outcomes in patients who
were treated with an alternative temozolomide schedule at
the time of failure on standard dose temozolomide. 13 Several
other alkylating agents (CCNU, BCNU) and other cytotoxic
chemotherapies (carboplatin, irinotecan, etoposide) are also
options for initial or subsequent progressions. Evaluation of
data from the control arm using CCNU at 100–130 mg/m 2
every 6 weeks from a recent phase III study demonstrated
a modest radiographic response rate (4.3%) but a relatively
good PFS-6 rate of 19%, 14 which was somewhat better than
the enzastaurin (experimental) arm (11.1%, p � 0.13) and
highlighted the potential activity of CCNU in this situation.
Very recently, the FDA approved a device, the NovoTTF-
100A system, for treatment of recurrent GBM based on a
randomized study demonstrating similar survival outcomes
in patients treated with this system compared with chemotherapy
of the physicians’ choice.
Antiangiogenic Therapies
Glioblastoma has long been recognized as a promising
tumor for antiangiogenic treatments because of its high
vascularity. Perhaps the most significant development in
the treatment of recurrent GBM in recent years has been
the development of antiangiogenic therapies and the FDA
granting of accelerated approval in March 2009 for bevacizumab.
Although this agent has altered the standard options
and approach for recurrent GBM, it has also become
increasingly clear that this treatment has limitations in
terms of disease control and requires clinicians to modify
their standard interpretation of MRI imaging and determination
of disease progression. This approval was based on
two independent phase II studies demonstrating activity.
15,16 Both studies showed a high radiographic response
rate and an improvement in 6-month PFS with bevacizumab
treatment compared to prior historic controls treated with
cytotoxic chemotherapies and other targeted agents. In the
multicenter BRAIN study, use of bevacizumab resulted in a
radiographic response rate of 28% (95% CI 18.5%, 40.3%)
and the median duration of response was 4.2 months (95%
CI 3.0%, 5.7%). 15 Bevacizumab treatment also resulted in an
increase in the percentage of patients treated with stable or
decreasing corticosteroid dosages. A second study reported
by Kreisl and colleagues demonstrated similar results with
single agent bevacizumab in which 29% of patients achieved
6 months of PFS. 16 Based on these results, two phase III
studies testing the addition of bevacizumab to temozolomide
chemoradiation in newly diagnosed GBM have been completed
or are in progress, with results expected within the
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