PSMA-PET/CT imaging in the EArly detection of Cancer of the Prostate with High Risk Features

PSMA-PET/CT imaging has gained wide attention as a superior staging modality in
men with PCa. Its diagnostic value has been well established for recurrent PCa
after initial curative treatment, and is currently investigated for its
(metastatic) staging potential of newly diagnosed high-risk PCa [1,2,3]. This
image modality has therefore altered diagnostic and treatment decisions, and
may presumably alter clinical outcome as well.

As of present, bone scintigraphy and CT scan of the abdomen is still indicated
as a staging tool for bone metastatic and/or regional lymph node metastases in
men with PSA * 20 ng/mL according to the Dutch urological guidelines and the
guidelines of the European Association of Urology (EAU).

The performance of PSMA-PET/CT imaging as a tool to select men with a suspicion
of potentially aggressive PCa for targeted instead of systematic biopsy, and
alternatively, to refrain from bothersome prostate biopsy in patients who may
not need it, is a scientific area that has not been investigated.

To assess whether PSMA-PET/CT imaging can be used as a tool to select men for
prostate biopsy, or otherwise is able to reduce the number of bothersome biopsy
cores in those with an increased risk of aggressive prostate cancer*

INTERVENTION.
In all men with PSA between 20 - 50 ng/mL, the 18F-PSMA driven diagnostic
pathway is applied. First, all men will undergo PSMA-PET/CT imaging before
diagnostic prostate biopsy. A *positive* for cancer 18F-PSMA-PET/CT will result
in 2-4 (targeted) prostate biopsies directed towards PSMA-avide areas in the
prostate. For ethical reasons, routine systematic prostate biopsies are taken
in the same biopsy session. A *negative* for cancer PSMA-PET/CT will result in
routine systematic prostate biopsies only. Ethically, it is not yet permissible
to withhold men with a *negative* for cancer PSMA-PET/CT a systematic prostate
biopsy.

IMAGING PROTOCOL 18F-PSMA-PET/CT
All studies will be performed on a Ingenuity Time of flight 64 slices PET-CT
scanner (Philips Medical Systems, Best, the Netherlands) with an axial field
per view of 18 cm. High-dose CT (HD-CT) will be collected using a beam current
of 50 mAs at 120 keV. CT will be reconstructed using an image matrix size of
512 x 512 resulting in voxel sizes of 1.17 x 1.17 mm and a slice thickness of 5
and 2 mm, respectively. For PET, data will be reconstructed by means of a raw
action ordered subset expectation maximization algorithm using default
reconstruction parameters. Time of flight information will be used during
reconstruction. Reconstructed images will have an image matrix size of 144 x
144, a voxel size of 4 x 4 mm and a slice thickness of both 5 and 2 mm.

All patients will undergo the standard 18F-PSMA image acquisition protocol at
our institution. No extra preparation is needed. A good hydration is required,
1L of water within 1 hour prior to performing the scan. Patients will be asked
to empty the urinary bladder before the scan. Two hours post-injection of a
standard activity of 300 MBq 18F-PSMA, HD-CT will be performed, followed by a
whole body PET from mid-thigh to the basis of the skull. The acquisition time
will be 4 min per bed position. The total acquisition time for the whole body
PET/CT will be, on average, 30 minutes.

IMAGE ANALYSIS
Data analysis will be conducted on the Department of Nuclear medicine of the
Amsterdam UMC, location VUmc. Reconstructed images will be transferred to
offline workstations. Data analysis will be performed using in-house developed
software tools. Foci with increased PSMA expression will be drawn on the
reconstructed PET images of the prostate. Similarly, suspected metastases
(i.e., increased PSMA expression incompatible with physiological tracer uptake)
will be drawn on the reconstructed whole-body PET images. Volumes of interest
will be determined using standardized methods, and will then be utilized for
calculating the standardized uptake value (SUV) measures corrected for body
weight. A *positive* for cancer 18F-PSMA-PET/CT within the prostate gland is
defined as intense uptake, exceeding the background of the normal prostate
tissue. A *negative* for cancer 18F-PSMA-PET/CT is defined as no uptake within
the prostate gland.

BIOPSY PROTOCOL
Prostate biopsy is routinely performed by transrectal ultrasound (TRUS). In
this, an ultrasound image is obtained of the prostate and a puncture line is
given in the transverse and sagittal plane (Figure 2). Unfortunately, most
prostate cancers are iso-echoic and cannot be differentiated adequately from
normal benign tissue.

Systematic prostate biopsies are therefore obtained from the peripheral zone of
the prostate. All hospitals perorm transrectal biopsies. The OLVG, the AVL and
the AMC hospital also perform transperineal prostate biopsies. Dependent on
prostate size, 8, 10, or 12 biopsy cores are taken for transrectal prostate
biopsy, that is 4, 5, or 6 on each side respectively. For transperineal biopsy
this amounts to 20-22 cores over the whole prostate.

Targeted prostate biopsies are taken *cognitively*. This technique has been
adopted from mpMRI directed and targeted biopsies in patients with an
indication for prostate biopsy. In this, the images on mpMRI are translated
cognitively into TRUS images, so that mpMRI suspicious lesions can be targeted.
Cognitive targeted biopsies have not been found inferior to mpMRI driven
biopsies, i.e. in which patients are situated in an MRI scanner and in whom
biopsies are performed MRI guided. PSMA driven targeted prostate biopsies are
performed in a similar manner to mpMRI targeted biopsies.

In those with PSMA-PET avide lesions, 2-4 additional (targeted) biopsies are
obtained by directing the puncture needle towards the area of interest.
Pathological analysis is performed on the prostate biopsy cores routinely in
which special attention is given to the location and the side of the prostate
of individual biopsy cores as well as on the identification of individual
targeted biopsy cores.

Potential issues of concern

* PSMA-PET/CT is associated with an additional radiation exposure of 8 mSv.
* Targeted extra biopsies will be performed in patients with PSMA avide lesions
on PSMA PET/CT scan

Previous exposure of human beings with the test product(s) and/or products with
a similar biological mechanism

* Previous men that had a PSMA-PET/CT scan did not have immediate negative
consequences because of a single radiation exposure
* Allergies to the nuclear tracer PSMA have not been reported as of yet.
* Previous men that underwent targeted biopsies along routine systematic
prostate biopsies in studies with mpMRI did not experience an increased rate of
complicated urinary tract infections or other complications such as hematuria

Analysis of potential effect

* The additional risk of risk can be calculated with the following validated
link: http://www.xrayrisk.com/calculator/calculator.php

In this electronic risk calculation used by radiologists and nuclear
physicists, the type of radiation examination, age, the number of exposures,
and the average dose is filled in.

Then the total effective dose is calculated, and the additional cancer risk,
compared to the baseline cancer risk.


For instance, a man of 65 years undergoing a PSMA-PET/CT will receive an extra
radiation dose of 8 mSv.

The additional cancer risk for this man is 0,0267% (one in every 3734), against
a baseline lifetime risk of 44.9%