Visualizing VEGF producing lesions in Von Hippel-Lindau disease

Von Hippel Lindau disease (VHLD) is an inherited autosomal dominant syndrome.
The commonest manifestations are cerebral and retinal hemangioblastomas, clear
cell renal cell carcinomas (RCC*s), pheochromocytomas and neuroendocrine tumors
of the pancreas. Patients with VHLD are characterized by a germline mutation of
1 allele of the VHL-gene, disease manifestations occur when the function of the
wild type allele is also lost. Absence of a functional VHL protein results in
transcription of pro-angiogenic growth factors, the most important being
vascular endothelial growth factor (VEGF). Patients with VHLD are routinely
screened for disease manifestations. Hemangioblastomas can remain dormant for
unpredictable periods of time or present with accelerated growth. Currently
there are no clinical, radiographic or molecular markers that can predict the
natural history of a given lesion.
Bevacizumab is a humanized monoclonal antibody against VEGF. At the University
Medical Centre Groningen, non-invasive in vivo VEGF imaging with radiolabeled
bevacizumab for application in patients has been developed. We hypothesize that
VEGF producing lesions in patients with VHLD can be visualized with
89Zr-bevacizumab PET imaging. When additional lesions are detectable with
89Zr-bevacizumab PET imaging, this modality can be a complementary diagnostic
tool to routine investigations. Quantifying VEGF might give prognostic
information on the behaviour of individual lesions and might assist in decision
making on which lesions should be excised and which lesions might respond to
angiogenesis inhibitors.

The primary objective is to determine if disease associated lesions in patients
with VHLD can be visualized with 89Zr-bevacizumab PET scans. Secondary
objectives are to explore if 89Zr-bevacizumab PET imaging can differentiate
progressive from non-progressive lesions in patients with VHLD and to explore
relationships between angiogenesis related biomarkers and endothelial
activation markers and 89Zr-bevacizumab PET uptake.

This is a feasibility study to evaluate 89Zr-bevacizumab PET scanning as a
diagnostic tool for imaging disease associated lesions in patients with VHLD.
Patients must have had routine MRI scans of CNS and upper abdomen within 4
weeks of inclusion. Patients will be injected intravenously with 37 MBq,
protein dose 5 mg 89Zr-bevacizumab at day 0. A PET scan will be done at day 4.
Standardized uptake values (SUVs) and Relative Tissue Uptake (RTU) in disease
associated lesions will be determined. After 6 months MRI scans will be
repeated.

Patients will be intravenously injected at 1 time point with 37MBq. Together
with the PET-CT this results in a radiation dose of 19,5 mSv. According to ICRP
62 this radiation dose falls in category III (moderate risk).
The risk of development of a secondary malignancy is small and clinically
likely not relevant.
Patients have to pay 2 extra visits to the hospital. Blood samples for
biomarkers will be drawn at 2 time points, one of these time points corresponds
with routine blood investigations and the other time point means an extra vena
puncture.
There is no direct benefit for the patients in this study. If 89Zr-bevacizumab
PET imaging however is a predictive biomarker for progressive lesions, future
patients can be spared serious morbidity because treatment can be offered
before lesion become symptomatic.