The effect of dexamethasone on the biodistribution of [3-N-11C-methyl]temozolomide in glioblastoma multiforme patients

Radiotherapy and temozolomide (TMZ) are expected to be the backbone of
treatment for patients with glioblastoma multiforme (GBM), and possibly also
for patients with other glioma subtypes, during the next decade(s). Apart from
(chemo-)irradiation and adjuvant courses of TMZ, the majority of glioma
patients are treated with corticosteroids in order to avoid peritumoral edema,
and approximately half of the patients are on anti-epileptic drugs (AED), such
as levetiracetam.
Although interactions with other drugs are suspected to affect the efficacy of
TMZ, hardly any quantitative data on this issue are available. Corticosteroids,
such as DXM, are thought to affect the levels of other drugs in the brain,
including TMZ, for example by causing a dramatic decrease in blood-tumor
barrier permeability. Secondly, DXM influences transcellular and paracellular
pathways that regulate transport of drugs over the blood-brain tumor barrier.
Thirdly, DXM increases P-glycoprotein- (P-gp) and breast cancer resistance
associated protein (BCRP)-mediated drug efflux activity in the blood-brain
barrier (BBB). A variety of cytostatic agents and many AEDs are substrates for
P-gp. Thus, interactions between TMZ, corticosteroids and AEDs at the P-gp
level may affect TMZ concentration in the brain and in glioma tumor tissue,
which may hamper its efficacy. Increased knowledge on the biodistribution of
TMZ will improve treatment by allowing to adjust TMZ dosage when, for example,
corticosteroids are prescribed.
Positron Emission Tomography (PET) offers an excellent opportunity to determine
biodistribution and pharmacokinetics of drugs such as TMZ, and for that reason,
PET is the ideal instrument to quantify the effects of co-medication, e.g. DXM.
Previous studies have demonstrated that PET-scanning of
[3-N-11C-methyl]temozolomide ([11C]TMZ) is a robust tool to analyse and predict
tissue drug concentrations in order to determine the most rational dosing
schedules of TMZ. When we will be able to visualize and quantify the effects of
corticosteroids on [11C]TMZ kinetics in GBM, this may contribute to the
optimalization of treatment schedules.
Furthermore, it is also important to assess the effect of DXM on the cerebral
blood flow (CBF), as studies on the effect of DXM on CBF have, so far, been
inconclusive.

(1) Determination of the effect of dexamethasone on the biodistribution and
kinetics of [11C]TMZ in GBM patients. (2) The effect of DXM on CBF. If there is
an effect of DXM on CBF: (3) The effect of blood flow in the brain on [11C]TMZ
uptake.

Single-centre proof of concept / feasibility study in humans.

One gift of 10mg dexamethasone between morning- and afternoon scanning session.

1) Radiation exposure
The radiation exposure of 1100 MBq [15O] H2O is approximately 0.5 mSv. The
radiation exposure of 370 MBq of [11C]TMZ is approximately 1.4 mSv. The
radiation exposure of a low-dose CT of the head is 0.25mSv. Therefore, each
patient will receive a total radiation dose of 4.3 mSv, which is below the
general accepted amount of radiation burden of 10 mSv. For comparison, the
natural background radiation dose in the Netherlands gives annual dose of 2 -
2.5 mSv.

2) Idiosyncratic reaction to the tracer
The injected mass of [11C]TMZ in this study is negligible. Side effects have
never been reported at tracer doses used in PET studies. Since the molecular
structure of [11C]TMZ is exactly the same as the molecular structure of the
drug TMZ (see IMPD of [11C]TMZ), pharmacology and pharmacokinetics are
comparable (see IB of TMZ). Subjects have already been treated with
(chemo-)irradiation and receive or have received adjuvant TMZ when included in
this study without major side-effects. Thus, the [11C]TMZ will certainly be
negligible compared to treatment doses. A physician will be present during PET
scanning.

3) Adverse events from a single gift of DXM
Most of the adverse events mentioned in the SPC of DXM are associated with
repeated doses and long-term use of DXM. The risk of adverse events from a
single gift of 10mg of DXM i.v. are low, and the occurrence of for example
insomnia or psychiatric disturbances, such as depression or psychoses is rare.
Furthermore, it is possible to have a hypersensitivity reaction after a single
gift of DXM. However, most participants have used DXM previously, for clinical
reasons, without experiencing hypersensitivity reaction. The chance of
developing such a response when using DXM (again) is negligible. Patients with
a history of hypersensitivity reaction to DXM will be excluded. If patients do
experience hypersensitivity reaction on DXM, 2mg tavegil (in 10 ml NaCl 0.9)
will be administered. A physician will constantly be present during the
injection of DXM and the PET scan procedure.

4) Intravenous and intra-arterial cannulation
There is a very small risk of infection and bleeding associated with
intravenous and intra-arterial catheters, which are prevented by proper
techniques.

5) Blood sampling.
Adverse effects of blood sampling will be minimised by exclusion of subjects
with low haemoglobin levels (Hb must be > 8 mmol / litre at the time of the
scan for males and be > 7,5 mmol / litre for females). No more than 300 ml
blood will be withdrawn during the total PET procedure and screening.