J Clin Oncol. 2007 Sep 10;25(26):4127-36.Stupp R, Hegi ME, Gilbert MR, Chakravarti A.
Oncology Center, Centre Hospitalier Universitaire Vaudois and
University of Lausanne, Lausanne, Switzerland.
has been considered resistant to chemotherapy and radiation. Recently,
concomitant and adjuvant chemoradiotherapy with temozolomide has become
the standard treatment for newly diagnosed glioblastoma. Conversely
(neo-)adjuvant PCV (procarbazine, lomustine, vincristine) failed to
improve survival in the more chemoresponsive tumor entities of
anaplastic oligoastrocytoma and oligodendroglioma. Preclinical
investigations suggest synergism or additivity of radiotherapy and
temozolomide in glioma cell lines.
Although the relative contribution
of the concomitant and the adjuvant chemotherapy, respectively, cannot
be assessed, the early introduction of chemotherapy and the
simultaneous administration with radiotherapy appear to be key for the
improvement of outcome. Epigenetic inactivation of the DNA repair
enzyme methylguanine methyltransferase (MGMT) seems to be the strongest
predictive marker for outcome in patients treated with alkylating agent
chemotherapy. Patients whose tumors do not have MGMT promoter
methylation are less likely to benefit from the addition of
temozolomide chemotherapy and require alternative treatment strategies.
The predictive value of MGMT gene promoter methylation is being
validated in ongoing trials aiming at overcoming this resistance by a
dose-dense continuous temozolomide administration or in combination
with MGMT inhibitors.
Understanding of molecular mechanisms allows for
rational targeting of specific pathways of repair, signaling, and
angiogenesis. The addition of tyrosine kinase inhibitors vatalanib
(PTK787) and vandetinib (ZD6474), the integrin inhibitor cilengitide,
the monoclonal antibodies bevacizumab and cetuximab, the mammalian
target of rapamycin inhibitors temsirolimus and everolimus, and the
protein kinase C inhibitor enzastaurin, among other agents, are in
clinical investigation, building on the established chemoradiotherapy
regimen for newly diagnosed glioblastoma.