18F-FDHT PET/CT for re-staging patients with recurrent of prostate cancer after radiotherapy; a pilot study

Prostate cancer is the most common type of cancer among men worldwide 1. In the
Netherlands, incidence and estimated deaths of prostate cancer in 2014 were
respectively 9926 and 2535 per 100.000 Dutch men (www.cijfersoverkanker.nl).
According to the Dutch guidelines of prostate cancer, patients with localized
prostate cancer (cT1-2 Nx-0 Mx-0V TNM classification 2009) can be divided in
three groups by local extent of the tumor (T stage), prostate specific antigen
(PSA) and histological profile described by Gleason score. These cancer
specifics classify the primary prostate tumor as either low, medium or
high-risk. Together with patient characteristics (i.e. wish of patient,
expected side effects, life expectancy and co morbidities), the risk
classification determines the definitive choice for either active treatment or
active surveillance. The current active treatment options are radical
prostatectomy (RP), external beam radiotherapy (EBRT) or brachytherapy2.
Alternative and emerging treatment options for patients with clinically
localized prostate cancer who are not suitable for RP, are cryosurgical
ablation of the prostate (CSAP) and high-intensity focused ultrasound (HIFU)
3-5.
Rising PSA levels after radiotherapy do not distinguish between local, regional
or distant recurrence (lymph nodes or bone metastasis). CT sensitivity for
detecting local recurrences or lymph node metastasis is low. Bone scan and CT
is only recommended in patients with BCR after radical prostatectomy when the
baseline PSA is high (>10) or PSA kinetics is high or a patient has symptoms of
bone metastasis. Bone scintegraphy has low specificity compared to newer tracer
assisted positron emission tomography (PET)/CT6. In addition, BS cannot measure
tumor activity and is not a suitable for follow-up of therapy response7. TRUS
is not reliable after radiation therapy to show local recurrence8-10. The
current new European guideline advices to re-stage patients with BCR, who are
potential candidates for local salvage therapy, either PET/CT or with
multiparameter MRI (mpMRI) of the prostate. mpMRI can also be used to guide
local salvage treatment and for biopsy targeting. Various studies showed that
sensitivity of prostate biopsies to proof local recurrence of prostate cancer
after radiotherapy is considered low11,12. In the concept guideline by the
Dutch Urology Organization about prostate cancer (version 2.1), is written that
PSMA PET/CT is proven to be just as good and maybe better than choline PET/CT,
and can therefore be used instead of choline in the clinical setting. This is
already in use since this year in many academic centers in the Netherlands,
where PSMA has completely replaced choline as PET/CT tracer. Link to new
concept guideline:
https://www.radiologen.nl/files/File/kwaliteit/Protocollen%20en%20richtlijnen/Ab
dominale%20Radiologie/2016%2002%2022%20MODULE%20PET-CT%20Richtlijn%20prostaatcar
cinoom.pdf.
Currently most centers shift from anatomic imaging techniques to
metabolic/molecular imaging for the detection of recurrent prostate cancer.
PET/CT with a radiolabelled choline can be used after radical prostatectomy for
restaging, but sensitivity and specificity depend on PSA value and is only
recommended in patients with PSA >1 ng/mL. After radiotherapy, the PSA cutoff
after which choline PET/CT is useful is unclear because of lack of data but PSA
kinetics seems to be a better predictor than PSA value alone, for detection
rate13.
Although choline PET/CT shows the potential of single step whole body imaging,
its accuracy will be limited as non-cancer specific tracer. Although choline
PET/CT is and was a good first tracer for single step whole body imaging, its
accuracy will be limited as non-cancer specific tracer. Crucial for targeted
imaging is the use of tracers that are specifically over expressed in prostate
cancer but low in normal cells. Prostate specific membrane antigen (PSMA) is
over expressed in most prostate cancers; thereby labeled PSMA proves to be more
accurate for restaging of localized prostate cancer after radiotherapy14. The
first prostate specific membrane antigen antibody 111In-capromab pendetide
(ProstaScint, Cytogen, Princeton,USA), which binds to an intracellular part of
the antigen showed disappointing results on detection of local recurrence in
patients with BCR after radiotherapy15,16. First studies on newly developed
PSMA tracers binding to the extracellular domain of the receptor showed that
68Gallium-PSMA PET/CT is highly specific in imaging prostate cancer. Hybrid
68Gallium PSMA-ligand PET/CT has a higher detection rate in recurrent prostate
cancer after radical prostatectomy (>90% at PSA levels >1ng/mL) than hybrid
PET/CT with other tracers. Tumor detection was positively associated with PSA
value and higher Gleason score17. Another study was published on detection
rates in patients with recurrent prostate cancer after different primary
treatment. In this study tumor detection was positively associated with
androgen deprivation therapy (ADT)18. However, these studies were retrospective
and used a heterogeneous patient population (mixing stages and recurrences
after different kinds of primary treatment) which makes the outcomes hard to
interpret18-20.
In our center, there are currently two studies who assess 18F-FDHT PET/CT for
predicting outcomes of treatments in different stages of prostate cancer.
18F-FDHT images the androgen receptor with high binding affinity and
selectivity21. Dehdashti et al demonstrated that metastatic and recurrent
prostate cancer lesions can be detected by 18F-FDHT PET22. The sensitivity on a
patient basis was 63% (12 out of 19 patients) and the sensitivity on a lesion
basis was 86% (24 out of 28 lesions identified by two conventional imaging
modalities)22. Larson et al found corresponding results. 18F-FDHT PET was able
to detect 78% (46 out of 59) of lesions identified by conventional imaging23.
Moreover, 18F-FDHT PET disclosed 17 additional, previously unknown foci of
tracer uptake most consistent with metastatic disease23.
The imaging technique that is advised for restaging patients with prostate
cancer by the European Association of Urology(EAU) guidelines is
multi-parameter magnetic resonance imaging (mpMRI). Parallel imaging techniques
combined give more information about different tissues en therefore can be used
for different diagnostic purposes. Diffusion weighted MRI (DWI) does not
require intravenous contrast and derives his imaging from differences of
motions between intra and extracellular protons24. The apparent diffusion
coefficient (ADC) is the quantitative parameter describing microscopic water
diffuse ability. Pilot data suggest that the ADC value could be a biomarker,
when compared to SUV in 11C-choline PET/CT 25. Dynamic contrast-enhanced MRI
(DCI-MRI) uses differences in time of contrast enhancement between benign
tissue and tumor, following intravenous administration of contrast26. DCE MRI
is a promising tool to detect local recurrence of prostate cancer after
radiotherapy. The enhancement of post-radiation fibrosis is slow, whereas
recurrent cancer is usually hyper vascular. When compared to T2 weighted
imaging (T2WI) DCE MRI showed higher specificity and sensitivity (ranges
between 64-93% and 60-97%) than T2WI (54-88% and 39-85%) for imaging recurrent
prostate cancer after EBRT10,27.
Accurate localization of recurrence prostate cancer is needed for appropriate
treatment selection (local salvage therapy or systemic therapy) Toxicity of
salvage treatments was observed in 30% of patients in all three treatments in a
study of Peters et al.(2010)28. Possible complications vary from mild lower
urinary tract symptoms to recto-anal fistula. These high toxicity rates make
the need for careful selection of patients for salvage treatment even more
essential. In a study performed in this center (not yet submitted) we found
that choline PET/CT for restaging scan in patients with biochemical recurrence
after radiotherapy, could not locate assess advanced disease in 617% of
patients, since this patientsey showed no biochemical response to salvage
cryoablation. In studies by Afshar-Oromieh et al. and Eiber et al 17,29 , PSMA
PET/CT was superior to radio labeled choline PET/CT. Together with our
retrospective findings, that choline is not able to identify the patients who
are eligible candidates for cryoablation, We want to perform a pilot
head-to-head study to determine accuracy and detection rate of in which we
compare 68-PSMA-PET/CT to 18F-FDHT PET/CT and determine accuracy of both scans
compare finding of FDHT PET/CT to the imaging modalities made in the contect of
standard care: d to standard from European guidelines; multiple parameter MRI
and 68 Ga-PSMA-11 PET/CT. The result of this pilot can hopefully lead to a
larger study, if 18 F-FDHT PET/CT shows promising results.

Primary Objective: To assess the detection rate of 18 F-FDHT PET/CT in men with
recurrent prostate cancer after radiotherapy who are candidates for local
salvage treatment.

Secondary Objective(s): To assess the detection rate and accuracy of 18 F-FDHT
PET/CT to imaging made in the context of standard care (mpMRI and 68 Ga-PMSA
PET/CT) in men with recurrent prostate cancer after radiotherapy who are
candidates for local salvage treatment.

n this study, a 18 F-FDHT PET/CT will be made. A multi-parameter MRI and 68
Ga-PSMA PET/CT will be made in the context of standard care and to be used as
reference standards, so accuracy of 18 F-FDHT PET/CT scan can be determined.
After the scan is made, the study ends for the subject. All scans will be made
in the University Medical Centre Groningen (UMCG).
Since this is a pilot study, we aim to include 20 men who suffer from
biochemical recurrence prostate cancer after primary radiotherapy. Biochemical
recurrence is defined as PSA of nadir + 2 ng/mL(Phoenix definition)30.

The result of PET/CT scan will not be communicated to the patient. FDHT report
will not be published in the patient file, and only be send and stored
anonymously by the study team. Therefore, any result of the scan will not lead
to further diagnostics and/or treatment changes.

To obtain written informed consent, patients will receive a brochure containing
necessary information about the study, procedures, risks and possible side
effects. Also logistics and an explanation about what patients normally
experience during each scan will be described in the brochure.

Subjects have to an additional PET scan combined with low-dose CT for
anatomical context.
For 18 F-FDHT PET/CT:
- Patients will be given an intravenous catheter (I.V.) for administration of
the tracer. The I.V. will be removed after administration and will therefore
give minimal discomfort and risk.
- Patients will have to lie still on their backs for approximately 20-30
minutes (depending on weight).
-18 F-FDHT PET/CT is a tracer with no documented risks when administered to
humans. Like all tracers, there is risk for an allergic reaction, for which a
medical doctor of Nuclear Medicine department is nearby during all PET/CT scans
in the UMCG. Possible risks of I.V.placement are hematoma, infection and
extravasation of fluid or tracer.
- The radiation burden for 18F-FDHT is 0.018 mSv/MBq. For the injected dose of
200 MBq the total radiation burden is approximately 3.6 mSv. The low dose CT,
which will be used for attenuation correction and anatomical co-registration,
has a radiation burden of approximately 1.9 mSv. Total burden is 5.1 mSv.