Ga-68-DOTA-(RGD)2 PET/CT: imaging angiogenesis in patients with arterio-venous malformations

Arterio-venous malformations (AVM) are one of the various Congenital Vascular
Malformations (CVMs) and are a result of a defect already present at birth.
There is a direct communication between arterial and venous vessels or via a
meshwork of abnormal vessels termed a *nidus*. AVMs can result in cardiac
failure, arterial insufficiency, chronic venous insufficiencies, lymphatic
overload due to venous hypertension, or more local effects such as ulcerations
and bleeding. Therapy often includes endovascular embolization therapy, aiming
a complete occlusion of the *nidus* or stabilizing the disease by preventing
bleeding or ulcerations and minimizing the progression while retaining the
quality of life. Inadequate treatment results in recurrence of the AVM lesion
and those lesions will again be treated with endovascular embolization therapy.
Patients undergo thorough follow-up during and after treatment, resulting in
invasive and complex treatment plans.

The mechanism of AVM recurrence is still unknown. However, angiogenesis and
vasculogenesis are considered to play an important role in AVM. With recent
progress in molecular imaging, non-invasive PET/CT imaging of angiogenesis
might contribute to improved understanding of the pathophysiology in AVM
lesions. If angiogenesis contributes to the development and growth of AVM
lesions, the addition of angiogenesis inhibitors to current therapeutic options
could improve treatment outcomes.

Radiolabeled RGD-based peptides can be used to non-invasively image
angiogenesis. Those RGD-peptides bind integrin αvβ3, which is expressed on
newly-formed blood vessels. Several preclinical experiments carried out by us
and other research groups have focused on using RGD-based imaging peptides in
oncological, cardiological, and other angiogenesis-related questions. The
potential of imaging AVMs with Ga-68-DOTA-(RGD)2 PET/CT in the clinical setting
remains unknown, but if successful it could have potential as a clinical tool
to characterize AVM lesions and it will give a better insight in the
pathophysiology of AVM lesions.

In this study we aim to evaluate the feasibility to image αvβ3 integrin
expression in AVM using Ga-68-DOTA-(RGD)2 PET/CT imaging.

The primary objective of this study is to assess the feasibility and safety to
image αvβ3-integrin expression in patients with AVM using Ga-68-DOTA-(RGD)2
PET/CT.

With this study the feasibility and safety of Ga-68-DOTA-(RGD)2 to image AVM
lesions will be determined in a prospective observational cohort study.
Patients that fulfil the inclusion criteria will be scheduled for a 10-minutes
static Ga-68-DOTA-(RGD)2 PET/CT scan. Ga-68-DOTA-(RGD)2 (100-200 MBq, 70 µg)
will be injected intravenously. Safety monitoring includes the recording of
adverse events, changes in vital signs, and blood measurements before, during
and after the injection of Ga-68-DOTA-(RGD)2. Vital signs will be evaluated at
baseline, 60 and 120 minutes after injection and includes blood pressure,
temperature, and heart rate. Blood samples (3 à 5 ml) will be drawn before and
after injection.

The risks associated with the radiolabeled peptide injection are low. Toxicity
tests have been performed in mice and no adverse reactions were seen. In each
patient, two blood samples (5 ml/sample) will be taken, before and after
injection to determine short and long time changes in basic metabolic
parameters (a complete blood test is performed). The combination of
Ga-68-DOTA-(RGD)2 and the low-dose CT will cause a radiation dose equivalent of
<=6 mSv to the patient, depending on the location of the AVM that will be imaged.

During normal work-up (standard of care) the patients receive a radiation dose
between the 1.5 mSv and 200 mSv, depending on the location of the AVM that is
treated (radiation dose of an embolisation therapy of an AVM in the lower and
upper extremities is approximately 1.5 mSv, the radiation dose during treatment
of an AVM in the abdomen is between 11-200 mSv, depending on the extent of the
lesion). The addition of the Ga-68-DOTA-(RGD)2 PET/CT scan will therefore not
cause a change in risk, patients with AVM lesions in the lower and upper
extremities will still be in category IIb, patients with AVM lesions in the
abdomen are in category III as defined by the International Commission on
Radiation Protection.
Diagnostics and treatment of the subject are not influenced by the outcome of
this study and therefore the patient will not directly benefit from
participation in this study. However, imaging angiogenesis could contribute to
improved understanding of the pathophysiology in AVM lesions and therefore has
potential to improve treatment options.