2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

of rapamycin (mTOR) inhibition, VEGFR inhibition (cediranib),
or poly (ADP-ribose) polymerase (PARP) inhibition
are either underway or in planning.
In summary, the pivotal clinical trial performed by the
EORTC and NCIC using radiation and temozolomide established
the current standard of care for patients with newly
diagnosed glioblastoma. Efforts to improve on these results
with intensification of the chemotherapy were unsuccessful.
Clinical studies have been performed or are underway to
determine whether there are synergistic therapies that can
further enhance outcomes for this patient population and
thereby establish a new standard of care.
Treatment of Recurrent Glioblastoma
The treatment of recurrent glioblastoma remains unsatisfactory.
Tumor resection for recurrent disease does not
appear to substantially affect either the 6-month progressionfree
survival rate nor overall survival from the time of
progression. 18 However, relief of tumor-induced mass effect
may be clinically beneficial and the confirmation of true
recurrence (rather than treatment-related necrosis or pseudoprogression)
may be extremely helpful in treatment decisions.
A wide variety of approaches have been studied for recurrent
glioblastoma. These include local strategies often requiring
a surgical procedure and systemic chemotherapy
treatments either as single agent or in combination.
Locoregional Treatment Strategies
A variety of treatment approaches have been tested targeting
the tumor directly, recognizing that spread of glioblastoma
outside of the nervous system is rare. Use of a
carmustine-impregnated bioerodable polymer was tested for
recurrent disease and in a placebo-controlled randomized
trial showed a modest, but statistically significant improvement
in the 6-month survival rate. 19 These findings led to
FDA approval, but this treatment approach is not used
widely today.
Attempts to improve delivery of agents directly to tumor
led to the institution of convectional enhanced delivery.
Intratumoral catheters delivering small volumes of fluid
under pressure have been shown to spread widely from the
point of infusion. This method was used to deliver cintredekin
besudotox (interleukin [IL]-13-PE38QQR, IL-13
pseudomona extoxin) in a series of clinical trials. Despite
strong preclinical data, there was no improvement in outcome
compared with the carmustine wafer in a phase III
clinical trial. 20 Alternative strategies are looking at using
convection-enhanced delivery for chemotherapies, particularly
those like topotecan that do not cross the blood-brain
barrier with systemic delivery. 21
Direct injection of vectors containing gene therapies has
also been evaluated. Preclinical studies using transfection of
the herpes thymidine kinase gene into tumor cells by using
a retroviral vector demonstrated high efficacy after administration
of acyclovir or ganciclovir. However, clinical trials
in both recurrent and newly diagnosed glioblastoma failed
to demonstrate efficacy, potentially the consequence of
poor vector delivery by using direct injection into the walls
of the tumor cavity. 22 More recently, replication-competent
viruses are being evaluated in clinical trials, potentially
reducing the problem of delivery with continued local pro-
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duction and spread of the virus. For example, the delta-24
virus, a replication-competent adenovirus that requires amplification
of the Rb pathway to replicate, is currently being
studied in a clinical trial. 23
Systemic Chemotherapy
Metronomic and dose-dense temozolomide. Dose-dense temozolomide
has also been investigated in patients with
recurrent glioblastoma. 24 Two alternative dosing schedules,
alternating weekly schedule or 21 consecutive days of a
28-day cycle, have been used most commonly. Several phase
II trials have evaluated the “21 of 28-day” regimen with
6-month progression-free survival rates ranging from 18% to
30% even in patients with prior temozolomide exposure.
Similarly, retrospective analyses of patients treated with
the “week on, week off ” dose-dense schedule with temozolomide
report a 6-month progression-free survival rate as high
as 36%. Both schedules are associated with a high rate of
lymphopenia, although this toxicity may be more pronounced
with the 21 of 28-day schedule.
Metronomic schedules of temozolomide have been evaluated
in a prospective clinical trial. 25 Temozolomide was
administered at low dose (50 mg/m 2 /day) continuously to
patients who had previously been treated with standard
dosing of temozolomide as a component of first-line treatment
(as described previously herein for newly diagnosed
glioblastoma). Interestingly, patients rechallenged after
early failure (� 6 months of adjuvant temozolomide) or after
a treatment-free interval experienced 6-month progressionfree
survival rates of 27% and 36%, respectively. Patients
with treatment failure during adjuvant treatment but more
than six cycles fared poorly. These results suggest that in
select subpopulations, re-treatment with temozolomide may
be effective.
Resistance modulation with PARP inhibitors. There is
increasing interest in exploring inhibitors of PARP as a
novel strategy to enhance the efficacy of temozolomide and
address the recent finding that recurrent glioblastomas
acquire either MSH6 mismatch gene–inactivating mutations
or hypermethylation of the promoter region leading to
reduced expression. 26 Several PARP inhibitors are in early
clinical trials, typically in combination with a variety of
temozolomide dosing schedules. The dose-limiting toxicity
is likely to be myelosuppression, supporting the need for
pharmcodynamic studies confirming maximal synergy of
PARP inhibition with temozolomide-induced tumor DNA
damage.
Nitrosoureas and other chemotherapy agents. Nitrosoureas
such as carmustine and lomustine were the standard
treatment for recurrent malignant gliomas but their
use steadily declined with the introduction of temozolomide,
which is better tolerated and rarely causes cumulative
myelotoxicity. There has been a recent resurgence of nitrosourea
use after the report of a 6-month progression-free
survival rate of 19% in patients with prior temozolomide
exposure. 27 Other chemotherapy agents such as irinotecan,
carboplatin, cisplatin and procarbazine are used but the
response rates in recurrent disease have been modest.
Targeted agents. As discussed previously, glioblastoma
has been classified into two types primarily on the basis of
genetic features. Although there is some similarity in genetic
alterations, such as loss of phosphotase and tensin
homolog on chromosome 10 (PTEN), loss of cyclin-dependent