Unravelling the invisible infiltrating component of glioblastoma using MRI and a strong iron-like bloodpool contrast medium?

The most common primary brain tumor - glioblastoma (GBM) - is invariably fatal
with median survival of 15 months(1, 2). Regions with high GBM cell density
promote the development of abnormal vasculature only as they proliferate
further(3), which can be detected and visualized with conventional
contrast-enhanced magnetic resonance imaging (MRI). However, before dense
proliferation, GBM cells actively and extensively infiltrate the surrounding
healthy brain tissue over relatively long distances along myelinated axons and
blood vessels, co-opting on oxygen and nutrient supply(3-5). Without damage to
the locoregional blood-brain-barrier (BBB) this GBM cell invasion cannot be
visualized by conventional or contrast-enhanced MRI(6-8). Visualization of
tumor spread is of crucial importance when treating patients suffering from GBM
as the success of tumor resection depends strongly on the extent of tumor
infiltration(9, 10). For instance, incomplete resection often results in tumor
recurrence(11). Thus, out-of-the-box MRI methods for visualization of
infiltrating brain tumors are needed. The infiltrative growth of GBMs around
existing vasculature slightly influences the local density of blood vessels.
One would be able to visualize this small decrease in blood volume if a very
strong blood pool contrast agent could be used.

This study has been transitioned to CTIS with ID 2024-514013-34-00 check the CTIS register for the current data.

1. Perform a feasibility study of USPIO neuro-imaging in healthy participants
(n=6)

2. Perform MR imaging of glioblastoma by use of a new Off Road multi-sequence
protocol (i.e., T1w, T2w, FLAIR, DWI/DTI, SWI, T1w- and T2*w post-USPIO images)
in 15 GBM patients.

3. Analyze the obtained images and characterize brain tissue using both a
quantitative and qualitative methodology to delineate regions of tumor
infiltration.

The design of this study regards a single-arm prospective observational study.
The intention is to include 15 patients who are believed to suffer from
glioblastoma preo-operatively and are scheduled to undergo neurosurgical
treatment and/or chemoradiation therapy.
Prior to the inclusion of patients, a feasibility study will be carried out in
six healthy participants. This is needed to optimize the dosage of USPIOs
administered for adequate imaging.

Patients will be informed about this study and its objectives by a nurse
practitioner/neurologist/neurosurgeon during regular consultations prior to
surgery. Patients who meet all criteria and are willing to participate will be
informed about this study and will receive a patient information letter (file
E1) after which they will have a reflection period. Patients will have the
possibility to consult an independent physician who is informed about the
protocol but not actively involved in this study. After a maximum of 5 days,
patients will be contacted to answer remaining questions. If they are willing
to participate, they will sign a written informed consent (file E2).

Patients who are willing to participate in this study will be referred to the
Dutch hospital where USPIO neuroimaging will take place (Radboudumc, Department
of Radiology and Nuclear Medicine). The images will be taken by employees of
Radboudumc Nijmegen; Department of Nuclear Medicine following the available
clinical protocols.
USPIO imaging of the brain will not delay the clinical progress of the patient
to receive SCS. After USPIO imaging, patients will receive normal clinical and
radiological follow-up and treatment schemes.

Adverse effects have been reported in most studies with ferumoxtran-10. Most of
these were most likely unrelated to ferumoxtran-10 or were of mild severity
(8). One case of anaphylactic shock resulting in death was reported. In this
case ferumoxtran-10 was administered undiluted and within only several minutes
as bolus injection. This patient also had a previous contrast reaction to
another contrast agent.

In the present study, low dose of ferumoxtran-10 will be administered very
slowly (>30 min) and diluted and subjects will be observed by a physician
during this period. If any sign of a contrast reaction should occur, the
administration of ferumoxtran-10 will be stopped and further medical steps will
be undertaken if necessary. If the side effects have disappeared and it is
medically justified, the administration of ferumoxtran-10 will be continued
very slowly. In our hospital, between 2014 and 2016, 310 prostate cancer
patients were administered the similar compound ferumoxtran-10 as we will use.
Adverse effects occurred in 2.6% (n=8) of all subjects included of which 7 were
considered contrast-related. Four patients experienced side-effects during
administration (mild low back pain, flushing, and nausea) and three experienced
a dry mouth after infusion was completed. All were considered minor effects and
disappeared after temporary interruption or resolved spontaneously within
several hours (8).

Conclusively, the administration of ferumoxtran-10 has been researched in many
studies and shown to only pose small risks, particularly with the
administration method (diluted, slow and under observation) that is employed in
the clinic at our department.

We therefore feel that the possible benefits of this study (non-invasive
visualization of tumor infiltration in GBM patients) outweigh the (small) risks
involved in administering ferumoxtran-10