in glioblastoma is predominantly due to a radio-
sensitization effect, from the use of an effective
alkylating agent, or both.39
Temozolomide is a member of the class of drugs
known as imidotetrazines. It was developed as
a less toxic alternative to precursor compounds
and exhibited excellent penetration into the central
nervous system.40,41 In 1999, it was first approved
in the United States for recurrent anaplastic astrocytoma.42 Following the positive results of an
international phase III trial for glioblastoma,21 concurrent TMZ and radiation therapy has become the
standard of care for patients with newly diagnosed
glioblastoma. This multicenter, randomized, controlled trial compared the efficacy and safety of
TMZ administered concurrently and following radiation therapy (RT) with RT alone in patients with
newly diagnosed glioblastoma. TMZ combined
with RT was more effective than RT alone, and
the combined treatment was well tolerated. Median
overall survival time (OS) was 14. 6 months in the
TMZ plus RT group as compared to 12. 1 months
in the RT alone group. Based on the results of
this study, the FDA approved TMZ in 2005 for the
treatment of adult patients with newly diagnosed
glioblastoma. TMZ has 100% oral bioavailability
and readily crosses the blood-brain barrier. It acts
by methylating the O6 position of guanine in DNA.
Mispairing of thymidine with the O6-methylguanine
results in DNA strand breakage and cell death.
TMZ is given orally at a daily dose of 75 mg/m2
for 6 weeks along with radiation therapy. Patients
completing chemoradiation without disease pro-
gression may proceed to receive adjuvant TMZ at
150 to 200 mg/m2 on days 1 through 5 of a 28-day
cycle. Although the trial limited adjuvant TMZ to
6 cycles,21 in clinical practice patients have been
treated longer if there is no disease progression.
Patients may receive Pneumocystis carinii pro-
phylaxis during the concurrent phase of treatment.
Adverse effects include myelosuppression, nau-
sea, vomiting, anorexia, constipation, and fatigue.
Hepatitis B reactivation has also been reported
with the use of TMZ.43,44
Bevacizumab is a novel humanized monoclonal
antibody targeting vascular endothelial growth factor (VEGF). This pathway is important for tumor
angiogenesis. The use of bevacizumab for newly
diagnosed disease is being evaluated in clinical
trials and therefore is not considered standard of
care at present.
ers in brain tumors?
MOLECULAR MARKERS IN BRAIN TUMORS
Identifying subsets of patients who may be more
likely to respond to a particular therapy is an im-
portant focus of brain tumor research. This is com-
monly done in the case of many other malignan-
cies, such as testing for estrogen, progesterone,
and HER2/neu receptors in breast cancer.
Anaplastic oligodendrogliomas have been reported to have a favorable response to chemotherapy (and radiation) if they are associated with
1p and 19q chromosomal co-deletions.45 Two prospective, randomized, controlled trials evaluated
the potential benefit of adding PCV chemotherapy
(procarbazine, lomustine, vincristine) to radiation
therapy alone as initial therapy.46,47 The long-term
analysis for both studies confirmed the importance
of 1p and 19q co-deletions as favorable independent prognostic factors.48,49
Patients with glioblastoma associated with O6-
promoter methylation experienced greater ben-