Ga-68-DOTA-(RGD)2 PET/CT: imaging angiogenesis in patients with low-flow vascular malformations

Vascular malformations are congenital anomalies of the vascular or lymphatic
system. These malformations can be classified as low-flow and high-flow
according to their hemodynamic characteristics. Arteriovenous malformations
(AVM) are high-flow due to the arterial blood flow pattern. Venous
malformations (VM) and lymphatic malformations (LM) are low-flow lesions. This
study focuses on low-flow vascular malformations.
With increasing age and length of the patient, the vascular malformation grows
as well, and shows no tendency towards spontaneous involution. Lesion-related
complications include pain, swelling, infections, hemorrhage or functional
concerns depending on the location of the vascular malformation. In order to
prevent lesion-related complications and to reduce the size of the lesion,
treatment is often indicated. Management options include surgery and
embolization therapy. Embolization therapy is favorable, but the treatment plan
is complex and invasive with multiple embolizations and thorough follow-up.
Moreover, recurrence or and residue with persisting complaints is common.
The exact mechanism of recurrence of a vascular malformation is still unknown.
However, angiogenesis and vasculogenesis are considered to play an important
role in formation and growth of vascular malformations. With recent progress in
molecular imaging, angiogenesis can be imaged using a non-invasive
68Ga-DOTA-(RGD)2 PET/CT scan. 68Ga-DOTA-(RGD)2 is a radiolabeled RGD-based
peptide that binds to αvβ3 integrin, which is expressed on newly-formed blood
vessels. After injection of 68Ga-DOTA-(RGD)2, the localization of the vascular
malformation can be imaged and uptake values can be measured. Assessment of the
uptake values and the dynamics in αvβ3 integrin expression after embolization
therapy might result in adapted management, considering a combination of
embolization therapy with angiogenesis inhibitors.

The primary objective of this study is to measure whether αvβ3 integrin
expression and tracer uptake values of 68Ga-DOTA-(RGD)2 change in patients with
(recurrent) low-flow vascular malformations after embolization therapy.

In this pilot study, included patients will undergo a 68Ga-DOTA-(RGD)2 PET/CT
scan twice. A 10-minutes static PET/CT scan is performed 60 minutes after
intravenously injection of 68Ga-DOTA-(RGD)2 (100-200 MBq, 70 µg peptide). This
procedure will be repeated after multiple embolization procedures or after the
last treatment in case of complete radiological response or relief of symptoms.

In each patient, one blood sample will be taken to determine whether liver- and
kidney functions are within the normal range. This venous blood sampling will
be performed during the screening procedure, which will preferably be scheduled
during a regular hospital visit and otherwise will be performed by the general
practitioner. In addition, the patient will come to the hospital for the PET/CT
procedure. During this visit, a history on general condition will be taken and
a venous cannula will be placed for injection of the radiolabeled peptide.
The risks associated with the radiolabeled peptide injection are low. Toxicity
tests have been performed in mice and no adverse reactions were seen. Placement
of the venous cannula can cause local bruising.
The combination of 68Ga-DOTA-(RGD)2 and the low-dose CT will cause a radiation
dose equivalent of 4.7-5.2 mSv to the patient, depending on the location of the
vascular malformation that will be imaged. During normal work-up (standard of
care) patients receive a radiation dose between 1.5 mSv and 200 mSv, depending
on the location of the vascular malformation that is treated (radiation dose of
an embolisation of a vascular malformation in the lower and upper extremities
is approximately 1.5 mSv, the radiation dose during treatment of a vascular
malformation in the abdomen is between 11-200 mSv, depending on the extent of
the lesion). The addition of the 68Ga-DOTA-(RGD)2 PET/CT scan will therefore
not cause a change in risk: patients with a vascular malformation in the lower
and upper extremities will still be in category IIb, patients with a vascular
malformation in the abdomen are in category III as defined by the International
Commission on Radiation Protection (ICRP).
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 of low-flow vascular
malformations and therefore has potential to improve treatment options.