Pilot study on the determination of therapy resistant areas within the tumor in patients with high-grade glioma by repeated 18F-FDG-PET-CT scans.

Patients harboring a primary intracerebral high grade tumor (WHO III- IV) have
a median survival of six to 12 months. Combined chemoradiotherapy with
temozolomide is now the standard of care since results of the joint EORTC-NCIC
phase III study randomizing between radiotherapy alone and combined
radiochemotherapy with temozolomide showed a significant improvement in 2-years
survival from 8% to 24% for the combined treatment arm (Stupp 2005).
A differentiation between possible responders and non-repsonders before the
start of irradiation may eventual be possible by the use of 18F-FDG PET-CT.
Preliminary own results have shown that a higher metabolic activity in
glioblastoma as measured on a simulation 18F-FDG PET-CT scan can be a
prognosticator for shortened survival (Baumert, 2006).
Our preliminary data show that a high uptake of 18F-FDG on a PET-CT scan before
radiotherapy in glioblastoma could be a marker for reduced survival.
Popperl et al showed that dual phase FDG PET imaging is superior in
differentiating low-grade from high-grade recurrent astrocytomas (Popperl,
2006). Visual analysis of delineation of glioma showed that the delayed images
(imaged first 0-90 min and once or twice later at 180-480 min after injection)
better distinguished the high uptake in tumors relative to uptake in gray
matter. SUV comparisons also showed greater uptake in the tumors than in gray
matter, brain, or white matter at the delayed times (Spence et al).
These findings support the view that by using FDG-PET scans we could image
active areas within the tumor. Indeed, in vivo, a cancer is made up by
different types of cells, including hypoxic cells, cells that proliferate more
fast, as well as by non-malignant tissues, including inflammatory cells and
vasculature.
Intra-tumor heterogeneity in malignant glioma is often oberserved and can be
visualised also by current PET-CT techniques.
The dynamics of the tracer uptake in the different tumor sub-volumes may give
important information about the biological characteristics as well. Indeed, the
dynamics of FDG uptake per cell are dependent on the blood flow, the uptake in
the cell and the phosphorylation. All these of these steps give information on
the biology of the cancer in that particular area of the tumor.

To determine the localisation within the primary tumor of the therapy resistant
cells, before and during radiotherapy to determine the accurate boost volume.
To determine changes during treatment intra- and extratumoral within the
irradiated area.(Intratumoral: change of up-take - decrease, increase, change
of localization/ Extratumoral: effects of temporal changes in up-take - e.g.
due to oedema).

Study design:
Patients treated with radical radiotherapy for a high grade glioma and
post-operative visible tumour will undergo:

Standard examinations:
- A first dynamic PET-CT scan, , with standard I.V. contrast before
radiotherapy (= simulation PET-CT scan acquisition). After FDG injection the
acquisition time starts and continous for ca. 60 minutes.
- An MRI planning scan

Additional examinations:
- A second dynamic PET-CT scan with standard I.V. contrast in week 2 of
radiotherapy.
- A third dynamic PET-CT scan with standard I.V. contrast at the end of
radiotherapy (after 60 fractions, 1 fraction a day, 5 fractions a week) in week
7.
- A fourth dynamic PET-CT scan with standard I.V. contrast 3 months after
radiotherapy.

- At each of these time-points, 10 ml of blood (1 EDTA tube) will be taken for
analysis of markers for hypoxia (osteopontin), inflammation (IL-6) and
angiogenesis (VEGF). These markers may give more insight in the biochemical
correlation of the imaging data (correlation with FDG uptake measured by SUV).

The extra burden for the patients, including the extra dual phase PET-CT scans
(meaning that the patient has to lie down on the PET-CT scan from the time of
FDG injection to the end of the examination which will take approximately 45
minutes, whereas in the standard situation FDG is injected, the patient in
lying in a bed for 60 minutes, thereafter the scanning is done) as well as the
serum samples will be mentioned by the physician. After 1-3 hours a second scan
is made.