The Effect of Radiotherapy and Temozolomide on the Tumor Vasculature and Stem Cells in Human High-grade Astrocytomas
The Effect of Radiotherapy and Temozolomide on the Tumor Vasculature and Stem Cells in Human High-grade Astrocytomas
The purpose of the current trial is to explore whether the standard treatment with
 radiotherapy and temozolomide affect the tumor vasculature in patients with high-grade
 astrocytomas. If vascular effects are identified, future clinical trials can be proposed
 wherein anti-angiogenic agents are added to increase patient survival.
Today's standard treatment with radiotherapy and temozolomide yields a life expectancy of
 1.5-3 years in patients with high-grade astrocytomas. Thus, there is a need for further
 therapeutic improvements in this patient population. The purpose of the current trial is to
 explore whether radiotherapy and temozolomide affect the tumor vasculature in patients with
 high-grade astrocytomas. If vascular effects are identified, future clinical trials can be
 proposed wherein anti-angiogenic agents are added to increase patient survival. Additionally,
 stem cells within malignant brain tumors is an important new area of research in this patient
 population, and investigations herein could contribute to identify new predictive markers and
 therapeutic targets.

 Primary objective: To assess the vascular perfusion and permeability characteristics of
 high-grade astrocytomas (anaplastic astrocytoma and glioblastoma multiforme) using dynamic
 contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients receiving radiotherapy and
 temozolomide. Furthermore to assess whether therapy-induced changes in tumor perfusion is
 correlated with progression-free survival.

 Secondary objectives:

 -  Analyze circulating endothelial cells in the blood by flow cytometry to explore whether
 these cells can be used as an indirect estimate of angiogenesis in high-grade
 astrocytomas

 -  Analyze tumor specimens from patients that have had their gliomas debulked before
 commencing therapy

 -  immunostaining of the tumor vasculature to assess microvessel density

 -  immunostaining for tumor stem cells

 -  flow cytometric assessment of dissolved tumor tissue to look for tumor stem cells

 -  Assess progression-free survival of all patients included in the study, in order to
 correlate the survival data with the above tissue sampling results.
Inclusion Criteria:

 -  Histologically confirmed primary high-grade astrocytoma, i.e. anaplastic astrocytoma
 or glioblastoma multiforme.

 -  Have a WHO performance status 0-2 and be able to undergo outpatient treatment.

 -  Age ≥18 years.

 -  No pregnant or lactating patients can be included.

 -  Patients must have radiographically documented measurable disease postoperatively. At
 least one tumor lesion must be unidimensionally measurable as follows:

 -  Tumor lesion > 10 mm on conventional MRI scan, T1-weighted series, after
 intravenous (i.v.) gadolinium chelate contrast.

 -  All diagnostic radiology studies must be performed within 28 days prior to
 registration.

 -  Absence of conditions making MRI scans impossible;

 -  Cardiac pacemaker

 -  Other ferromagnetic metal implants not authorised for use in MRI such as some
 types of cerebral aneurysm clips

 -  Serious claustrophobia

 -  Obesity (> 300 lb., 140 Kg)

 -  Patients who are receiving corticosteroids have to receive stable or decreasing doses
 for at least 14 days before entering the trial.

 -  No prior chemotherapy for high-grade astrocytoma

 -  Absence of opportunistic infections making temozolomide contraindicated.

 -  Minimum required laboratory data:

 -  Hematology:

 -  Absolute granulocytes > 1.0 x 10^9/L

 -  Platelets > 100 x 10^9/L

 -  Biochemistry:

 -  Bilirubin < 1.5 x upper normal limit

 -  INR < 1.5

 -  Serum creatinine <1.5 x upper normal limit

 -  Adequate cognitive function in order to give informed consent.

 -  Absence of any psychological, familial or sociological condition potentially hampering
 compliance with the study protocol and follow-up schedule; those conditions should be
 discussed with the patient before registration in the trial

 -  Before patient registration/randomization, written informed consent must be given
 according to national and local regulations.

 Exclusion Criteria:

 -  Lack of fulfillment of inclusion criteria.