Optimisation of [68Ga] PSMA-11 PET/CT Imaging Protocol for localizing primary prostate cancer prior to radical prostatectomy

Prostate Specific Membrane Antigen (PSMA) is a epithelial cell surface
trans-membrane protein. It is overexpressed in prostate cancer, but is also
present in normal prostate cells, kidney, liver, salivary glands and upper
large intestine. This protein can be labelled to different radionuclides, but
most experience has been gathered with Gallium-68 (68Ga). The PSMA-inhibitor
Glu-NH-CO-NHLys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA-11) was developed by the
group of Afshar-Oromieh et al. in Heidelberg. Numerous studies in recurrent
prostate cancer showed that PSMA PET/CT is superior to an older phospholipid
derivate used in molecular imaging of prostate cancer; choline PET/CT. Although
the first studies on PSMA PET/CT focused on recurrent prostate cancer, PSMA
PET/CT(or MRI) is currently also used and studied in primary prostate cancer,
with encouraging results. There are a lot of treatment methods available for
patients with prostate cancer, ideally we would be able to monitor treatment
response. Because PET/CT images both in vivo anatomical and metabolic
information it can be the ideal imaging bio-marker. To serve as a biomarker, 68
Ga-PSMA PET/CT results have to be quantified. The primary goal of this study is
to find the optimal model that fits the pharmacokinetics of 68 Ga-PSMA-11
PET/CT, so that simplified quantification methods can be found. It is important
to validate simplified quantification mehods, as there is need to monitor
disease and treatment response in-vivo, without invasive treatment, to make a
tailored individualized therapy approach possible in prostate cancer. The
validity and repeatability of the simplified quantification method will then be
tested as secondary aim of this study. Because this study will be performed in
patients who will undergo prostatectomy, we will also be able to compare the
properties of 68 Ga-PSMA PET/CT to localize intraprostatetic cancer lesions to
the current standard, multi-parameter Magnetic Resonance Imaging (mpMRI).
According to a recent meta-analysis, MRI has a high specificity for localizing
primary prostate cancer. However, a relative poor sensitivity was shown,
especially for extrapostatic growth.

The primary objective is to determine the optimal pharmacokinetic model of
68Ga-PSMA PET/CT, so 68Ga-PSMA PET/CT results can be quantified in prostate
cancer.
The secondary objectives are to determine whether the optimal kinetic model of
68Ga-PSMA PET/CT is valid (by a repeatability test) and to see if 68Ga-PSMA
PET/CT could be a feasible method to exactly localize the tumour within the
prostate.

A monocenter, prospective observational study in 20 patients with primary
prostate cancer. The study consists of two parts: part A, to determine the
tracer kinetic properties and the optimal pharmacokinetic model to quantify and
identify 68Ga-PSMA uptake, to assess which (perfusion independent)
pharmacokinetic parameter best reflects presence of tumour and to validate
simplified (quantitative) metrics that can be used in a clinical setting. The
optimal model and quantitative analysis will be used in part B, to determine
whether 68Ga-PSMA is able to exactly and repeatedly localize the tumour within
the prostate, prior to radical prostatectomy. Patients participate in either
part A or part B, never both.

A. In the first part, both PSMA (68Ga-PSMA) uptake and perfusion (H215O) will
be measured quantitatively. Eight patients will be injected with two tracers:
H215O and 68Ga-PSMA followed by dynamic scans of one bed position, namely the
pelvis. Accuracy of blood and plasma activity concentrations, plasma metabolite
measurements derived from arterial and venous samples as well the reliability
of using Image Derived Input Functions (IDIF) for quantification of 68Ga-PSMA
kinetics will be tested.

B. In the second step of the protocol, depending on the obtained validation in
part A, the clinically feasible imaging procedure will be used in 12 other
patients, e.g using a simplified 68Ga-PSMA PET-CT imaging study, in aim to
visualize the location of the primary tumor within the prostate. Repeat PSMA
PET/CT scanning will be performed in these 12 patients, to evaluate test-retest
repeatability in tumor tracer uptake and localization.

For this imaging study patients have to make 1 (part A) or 2 (part B) extra
visits to the clinic to receive tracer injection and to undergo 2 PET scans.
Part A implements a radiation burden of 4.1 mSv, part B of 9.4 mSv. See
appendix K6.
For PET imaging in part A, patients will be given a radial artery
cannula, which will give minor discomfort and with possible side effects of
hematoma and infection. Based on previous research, we consider that the risks
are negligible and the burden will be minimal. A total of 250 ml blood will be
taken during the scans of part A. Patients that use anticoagulants are excluded
from part A of the study to minimize risks.

Radiation burden 68Ga-PSMA PET = 3.2 mSv. Radiation burden 15O-H2O PET = 0.4
mSv.
Part A: low-dose CT scan one bed position (21cm) of the pelvis with a total
radiation burden 0.5 mSv. Part A : Etotal = 4.1mSv

Part B: Patients will undergo two whole-body 68Ga-PSMA PET/CT scans.
For attenuation correction there will be a low-dose CT scan gemaakt from head
to halfway femur with a radiation burden of 1.5 mSv. Part B: Etotal = 9.4 mSv

According to ICRP(International Commission on Radiological Protection) 62, This
study falls under category 2B.