Imaging Radiotherapy-induced brain injury using advanced MRI and PET, a pilot

Radiotherapy-induced brain injury can clinically manifest as cognitive decline
and neurobehavioral impairment and is considered irreversible in the chronic
phase, affecting patients* quality of life [1][2]. The suspected mechanisms of
cognitive decline seem to be complex and probably triggered by early
microvascular damage causing disruptions in blood flow and improper blood-brain
barrier function, loss and dysfunction of oligodendrocytes, damage and
dysfunction of astrocytes, delayed neurogenesis, inflammation,
neurodegeneration and microanatomical abnormalities and therefore, neuronal
dysfunction [3]. Cognitive decline occurs within months or years after
radiotherapy [1-3]. So far, no validated imaging tools are available for
assessing the risks of acute and/or chronic brain damage caused by
radiotherapy. This is especially true for the areas affected by lower
non-therapeutic radiation doses. Having a biomarker for radiotherapy damage
would possibly create an opportunity to modify an ongoing treatment and open
the door for research on preventive treatment. Several MRI techniques, such as
Susceptibility Weighted Imaging (SWI), Quantitative Susceptibility Mapping
(QSM), vessel architectural imaging (VAI), Arterial Spin Labelling (ASL),
Synthetic MRI (synMRI) and Diffusion Kurtosis Imaging (DKI) have the potential
to visualize microvascular changes and white matter changes, especially when
combining findings of several individual approaches. Furthermore, metabolic
brain changes, neuroinflammation and neurodegeneration can be monitored by
respectively [18F]FDG PET, [11C]UCB-J PET and [11C]PK11195 PET.
Therefore, in this pilot study we want to look at different aspects of
radiation damage, including effects on microvasculature, blood-brain barrier
function and white matter changes. We hypothesize that combining these
different imaging modalities (MRI and PET) with advanced post-processing will
increase the understanding of in vivo changes resulting from
radiotherapy-induced injury and will allow the detection of
radiotherapy-induced brain injury at an early stages. We also hypothesize that
early detection of changes (or lack thereof) will be predictive of (later)
cognitive outcome assessed by neurocognitive function test.

Primary Objective: Is detection of the early brain changes, including
microvascular and white matter radiotherapy-induced changes, possible already
during radiotherapy treatment by means of combining novel MRI and PET
techniques and post-processing methods in patients treated for head and neck
tumours.
Secondary Objective(s): Is there an association between the early brain damage
demonstrated with MRI and PET imaging with the subsequent occurrence later
brain damage on MRI and PET and cognitive and neurobehavioral changes in
patients treated for head and neck tumours?
Have patients that received proton therapy less brain damage than patients with
photon therapy?

Study design: Observational pilot study.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: Participants undergo standard clinical
diagnostic and treatment procedures from which data will be used for the study.
In addition to that: 3 neurocognitive assessments will be performed; 1
routinely planned clinical MRI scans with intravenous contrast agent will be
upgraded with additional MRI sequences, which will extend the scanning time by
20 min (total scan time 55 minutes); 4 additional MRI scans with intravenous
contrast agent will be performed new sequences only (20 minutes). One group (10
proton and 10 photon patients) will undergo 2 additional FDG-PET scans in
addition to a standard clinically performed PET scan. Another group group (10
proton and 10 photon patients) will undergo 3 additional [11C]UCB-J PET and
[11C]PK11195 PET scans.
The study will consist of 5 visits:
- baseline visit within 2 weeks before the start of radiotherapy
(clinical-research visit combined)
- 2 weeks after the beginning of radiotherapy (research visit only)
- directly after the end of radiotherapy (research visit only)
- 3 months after the end of radiotherapy (clinical-research visit combined)
- 1 year after the end of radiotherapy (clinical-research visit combined)
The risks associated with the study are relatively low and result from the
standard procedures of arterial and venous injections for the MRI and PET
scans. The only adverse event can be a bruise as a result of the catether
insertion for the MRI and PET scans. According to the International Commission
on Radiological Protection (ICRP62) the radiation level of the first group will
be 7.8 mSv and for the second group 15.8 mSv, which are in respectively
category 2b and 3. However both groups also receive therapeutic radiotherapy,
these risk can be considered neglectable.
The subjects will not directly benefit from the study, but will help to
evaluate brain damage after proton and photon radiotherapy. This can lead to
additional studies leading eventually to improved diagnosis and new treatment
strategies.