[18F}-gelabeld FDHT in PET/CT voor detectie en stagering van ossale metastases in hormoon naïeve prostaatkanker.

Bone scintigraphy, CT, [18F]FDG and [11C] and [F18]-choline PET and magnetic
resonance imaging (MRI) are imaging modalities used to determine the extent of
prostate cancer both in the primary tumor and in metastases. During therapy,
some of these imaging tests can also be used to monitor progression or
regression of disease.

For detecting lymph node metastasis, the sensitivity for CT and MRI is 42 en 39
percent respectively, with a specificity of 82 percent.1
Using PET with [18F]-labelled FDG as a radiotracer, cellular metabolism can be
visualised and localised, when combining the PET with CT. Cancer in general has
a high metabolism, thereby leading to increased uptake of FDG. However, there
is also an increased physiological FDG uptake in inflamed tissue PET scanning
itself is relative insensitive for detecting regional lymph node metastasis in
prostate cancer, which probably reflects low metabolic activity within prostate
cancer cells.. In organ confined disease, FDG PET has only a sensitivity of 4
percent.2 In metastasised disease, FDG-PET resulted in an overall sensitivity
of 65%.3 Looking at osseous lesions, FDG PET tends to indentify only those
lesions with an aggressive prostate cancer in it, which causes high
osteoclastic activity, which in turn has a higher uptake for FDG. This is not
the case is slowly progressive bone disease.4 One study showed a sensitivity of
34% for bone metastasis in patients with PSA recurrence.5 [11C] and
[18F]-choline PET are mostly useful for restaging prostate cancer; to localize
lesions that are unrecognised clinically or on conventional imaging
techniques.6,7
Altogether CT, MRI, and FDG PET have a fairly low sensitivity for detecting
prostate cancer, and bone scintigraphy is the *gold standard* used to detect
osseous lesions, however with low specificity.

Patients with metastasized prostate cancer are treated with androgen
deprivation therapy, since androgens are the driving force behind disease
progression. When patients are treated with androgen deprivation therapy, the
cancer usually goes into regression. After 2-3 years, the cancer progresses
again despite an androgen free environment. Studies have shown that androgen
receptor expression is very low in these tumours, and that the cancer starts
growing via alternative pathways.

In this pilot study, we study PET/CT scans in patients with hormone naive
prostate cancer, using a targeted radiotracer: [18F]Fluoro-Dihydrotestosterone
([18F]FDHT). Several imaging studies have been published about this new tracer
that show promising results. Dihydrotestosteron (DHT) is the most active
metabolite of testosterone with a high intracellular uptake in prostate cancer
cells. We try to evaluate the feasibility of [18F]FDHT as a radiotracer in
subjects who did not received androgen deprivation therapy yet. Secondly we
want to investigate differences in uptake in lesions after start of androgen
deprivation therapy by performing a second [18F]FDHT PET three months after
start of ADT. We hypothesize that after start of androgen deprivation therapy,
the AR will be upregulated and therefore the standardized uptake value in the
lesions will increase.
[18F]FDHT PET could be used to assess the extent of prostate cancer to monitor
therapy response and to identify patients that have low androgen receptor
expression, who are prone to respond worse to androgen deprivation therapy. For
the latter, other therapeutic regiments could be initiated earlier.

Primary Objective: the primary objective of this study is to determine the
feasibility of [18F]FDHT PET/CT for in vivo evaluation of bone metastases in
prostate cancer. Active locations will be compared with those seen on
conventional imaging (bone scintigraphy, CT and/or MRI)

Secondary Objective(s): the secondary objective is to determine differences in
uptake in lesions using [18F]FDHT PET/CT three months after start of androgen
deprivation therapy.

This pilot study compromises two phases:
• the first phase is to assess [18F]FDHT PET/CT as a marker for detecting
advanced hormone naive prostate cancer lesions, compared to all lesions seen on
bone scintigraphy, CT and/or MRI
• The second phase is to determine differences in uptake in lesions using
[18F]FDHT PET/CT three months after start of androgen deprivation therapy and
it's relation with Gleason Sum Score and initial PSA.

Candidates for this study imaging study are subjects with metastasized prostate
cancer,
• confirmed by positive bone scan, suspicious lesions >=2 in bone.
• who have not been treated with androgen deprivation therapy yet.
• Who do not require require immediate start of androgen deprivation therapy
because of imminent pathological fractures or spinal cord lesion

For the first phase, one [18F]FDHT PET/CT will be performed to get a baseline
scan after informed consent has been given by the patient. After this scan,
patients will start androgen deprivation therapy as is standard in these
patients. They will be treated with LHRH analogues or via surgical castration,
that do not interfere with the occupancy of the androgen receptor. Patients
will not receive anti-androgens, because these cause a competitive antagonism
on androgen receptor level, which could interfere with binding of the
[18F]FDHT.

During the second phase, subjects will be scanned a second time, 3 months after
start of androgen deprivation therapy, in order to monitor occupancy of the
androgen receptor, which is indicative of potential treatment efficacy..
The subjects will be gathered by urologists or urology residents via the
University Medical Centre Groningen. Referring hospitals will also be informed
in order to gather a sufficient sample size within 12 months.

To obtain informed consent, patients will receive a brochure containing
information about this study, investigational procedures, possible side effects
and the logistics concerning the scanning, in addition to the information the
patient already has received on the outpatient department from a urologist.

For the first scan subjects will get an indwelling venous catheter for
administration of [18F]FDHT PET/CT. Subjects will also be given a urinary
catheter. The main reason for this is that a bladder filled with [18F]FDHT and
its metabolites could compromise the imaging in the pelvic area , which is why
the bladder has to be empty during scanning.
Although [18F]FDHT has been studied in clinical pilot studies before without
reporting of side effects, we will monitor adverse reactions in this protocol
as we have used a new synthesis protocol for the tracer.
To identify adverse reactions to the infusion (e.g. anafylaxia) as early as
possible, patients will be monitored via pulse oximetry and blood pressure
measuring at certain points (before scanning, 10 minutes after administration
[18F] FDHT, and after scanning).

Patients will receive a total dose of 200 MBq of [18F]FDHT. After the
administration, patients have to wait for one hour. After that the patients
will be placed in the PET/CT camera (Biopgraph mCT, Siemens Medical Systems,
Knoxville, Tennessee, U.S.A.). After scanning, the patient will be observed
shortly either at the radiology department or urology department, to see
whether any side-effects occur. When no adverse reaction occurs, the indwelling
intravenous catheter will be removed, and so will be the urinary catheter. When
the patient is able to micturate, he can return home.

The procedure for the second scan is the same as the first scan.

The PET scans results will be reported by a nuclear medicine physician. All
suspected lesions will be noted, both in lymph nodes and in bone. Using the
SUV, uptake in lesions will be calculated by the principal investigator of this
study.

Then, the PET scans will be compared to bone scintigraphy, CT and/or MRI. The
locations of the lesions will be compared to evaluate the similarity between
[18F]FDHT PET/CT and the other imaging studies.

For the second phase the images of the second [18F]FDHT PET/CT will be compared
with the initial [18F]FDHT PET/CT. Again, the SUV will be calculated lesion by
lesion for the second scan. After that, SUV*s in the first and second scan will
be compared in order to determine whether androgen deprivation therapy was
effective for the individual subjects. Statistical analysis will be performed
using SPSS Statistics version 21.

The burden of this study outweighs the possible benefits of the study in all
prostate cancer patients. This study could lead to improved imaging resulting
in a more patient specific treatment plan, or possibly treating with curative
intent, in those otherwise treated palliative (and vice versa). Another
possible results of a new tracer could be to monitor therapy response in
patients, in order to see in an earlier stage who is responding to treatment
and who is not. This way, non-responders can quit therapy and its side effects.