Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma
Status:
Completed
Trial end date:
2009-05-01
Target enrollment:
Participant gender:
Summary
Glioblastomas represent 40% of all tumors of the central nervous system (CNS) and are among
the most lethal tumors. Temozolomide (TMZ) combined with radiotherapy was the first substance
to significantly improve the overall survival (to 14.6 months) as compared to surgery and
radiotherapy alone and increased the proportion of patients surviving more than 2 years to
26%. TMZ showed the best efficacy in patients with a methylated O6-methylguanine-DNA
methyltransferase (MGMT) promoter in part by eliminating stem cell-like tumor cells. Among
patients with a methylated MGMT promoter, the median survival after treatment with combined
radio-chemotherapy was 21.7 months, as compared to 15.3 months among those who were assigned
to radiotherapy only. In the absence of methylation of the MGMT promoter, there was a smaller
and statistically insignificant difference in survival between the treatment groups.
Doxorubicin is one of the most effective substances in vitro against cells derived from
glioblastoma. However, it has no significant effect in vivo due to poor blood-brain-barrier
penetration. In a tumor model, tissue and CSF-concentrations of doxorubicin were
substantially increased when sterically stabilized liposomes were used resulting in a
comparable clinical response using approximately half of the dose of stabilized liposomes
compared to conventional doxorubicin. A pegylated formulation (PEG-liposomal Doxorubicin)
even further improved the penetration of the blood-brain barrier. Case series and two phase
II-studies in patients with recurrent glioblastoma have shown modestly promising results for
PEG-Dox.
In this study, the investigators treated patients with recurrent glioblastoma with 20 mg/m2
PEG-Dox on days 1 and 15 of each 28-day cycle. To determine the dose limiting toxicity of
PEG-Dox combined with prolonged administration of TMZ, the investigators performed a phase I
part ahead of the phase II study. To investigate, by means of a historical control analysis,
if the addition of PEG-Dox to TMZ and radiotherapy improves the survival of patients, the
investigators chose similar inclusion criteria and identical TMZ and radiotherapeutic regimes
as in the EORTC26981/NCIC-CE.3 study.