Prospective, single-centre, feasibility study to evaluate the use of 18F-PSMA PET/CT in patients with biochemically active medullary thyroid cancer.

More than 10% of patients with medullary thyroid carcinoma have distant
metastases at initial presentation1. Diagnostic procedures are necessary to
determine the extent of disease and the extent of the initial surgical
approach. 18F-FDG is the most widely used tracer to evaluate the presence of
distant metastases. It accumulates in cancer cells due to their high glucose
metabolism. In MTC, it has an overall sensitivity of 62-76%, with higher uptake
in patients with aggressive tumors (calcitonin-doubling times <9 months) 2,3.
However, this method is less appropriate in patients with indolently growing
tumors. The other molecular imaging modality that is used in MTC, is the
18F-DOPA PET. This tracer binds to an amino acid transporter after which it is
metabolized in the catecholamine pathway that is commonly active in
neuroendocrine tumors 4. In contrast to the 18F-FDG PET, it shows a better
performance for indolently growing MTC with low calcitonin doubling-times.4,5
However, 18F-DOPA is not as widely available as 18F-FDG, e.g. due to lack of
commercial availability, and/or higher costs compared to 18F-FDG. Therefore,
there is a need to explore additional tracers for (re)staging patients with
MTC.

A tracer that is worth exploring is 18F-PSMA, targeting the prostate specific
membrane antigen (PSMA). PSMA is a transmembrane protein found on the apical
membrane of virtually all prostate cancer cells. Multiple PSMA-directed
radio-labelled tracers have been developed for PET scanning. 18F-PSMA and
68Ga-PSMA are both used in clinical practice to detect (recurrent) prostate
cancer. They have been compared but neither is clearly superior6. In the UMCG,
the 18F-PSMA-1007 tracer has been used since mid-2019. This tracer has
demonstrated high tumor uptake, creates high contrast to background images and
does not have physiological uptake in the thyroid gland, as demonstrated in
previous studies for prostate cancer patients. Moreover, its relatively long
half-life allows transportation, improving its accessibility in medical centers
without a cyclotron on-site7.

PSMA was thought to be very specific for prostate cancer. However, the past
decades multiple studies have reported the expression of PSMA in the
neovasculature of several other solid tumors, including MTC8. A recent
pathology study showed PSMA expression in 92% of >100 included specimens of MTC
patients 9. Moreover, there are case reports that incidentally found thyroid
tumors after focal uptake in the thyroid on a 68Ga-PSMA PET or 18F-PSMA PET for
prostate cancer staging8,10,11. Currently a clinical trial is studying
68Ga-PSMA uptake in thyroid cancer in general (clinicaltrials.gov; NCT03463889)
highlighting the relevance to study a PSMA directed tracer in thyroid cancer
patients. It is unclear whether the study also includes medullary thyroid
tumors. Thus far, no clinical trials have been registered studying 18F-labelled
PSMA in MTC patients.

Therefore, this feasibility study will evaluate whether the 18F-PSMA PET/CT is
capable of MTC lesion detection. Moreover, we will compare its ability to
detect MTC lesions with a routinely used PET scan, the 18F-FDG PET. By
exploring new tracers in PET scanning for MTC, we aim to ultimately 1) improve
disease staging in the primary diagnostic process to adjust treatment
accordingly (e.g. establish extent of surgery) and; 2) improve the detection of
disease progression in the follow-up (e.g. allowing treatment of an
oligometastasis or support decisions to start systemic therapy).

This study will be a single-center feasibility study to evaluate the clinical
value of the 18F-PSMA PET/CT in patients with medullary thyroid carcinoma.
After ethical approval of the study, inclusion will start and 10-15 patients
will been included until the end of 2024, until 15 patients have been included.
The entire study will take place in the UMCG.

Patients are eligible when diagnosed with MTC and when an indication for an
18F-FDG PET/CT is present 1) during the work-up for disease extent in the
primary diagnostic process, prior to (surgical) treatment or 2) during
follow-up, to evaluate for the presence of disease progression or recurrence.
Patients will subsequently be informed and asked for inclusion in the study by
their treating physician, during their outpatient appointment. If patients have
not sent their informed consent form within two weeks after this appointment,
patients will be approached by the coordinating investigator and asked for
written informed consent.

The 18F-FDG PET/CT and 18F-PSMA PET/CT will be planned on different days,
requiring patients to come to the hospital one extra time. The order of the two
scans is not relevant and therefore dependent on availability in the clinic.
Both scans will be performed on the same camera in the Medical Imaging Centre
of the UMCG to allow adequate comparison. The 18F-FDG-PET/CT is part of routine
clinical patient care. Patients will need to make one additional visit to the
UMCG for the 18F-PSMA PET/CT.

The 18F-PSMA PET/CT will be analyzed in two steps. Firstly, the nuclear
medicine specialist (Dr. A.H. Brouwers) will be blinded from patient/clinical
information when analyzing the 18F-PSMA PET/CT. Afterwards, all information
will become available to the nuclear medicine specialist, including the results
of the 18F-FDG PET/CT, and the 18F-PSMA PET/CT will be re-analyzed. Lesions
will be considered abnormally avid when there is uptake above normal background
activity which cannot be attributed to the known physiological uptake pattern
of 18F-PSMA uptake.

The results of the 18F-PSMA PET/CT will be compared with the 18F-FDG PET/CT.
Other potentially available radiological imaging studies performed as part of
clinical practice will also be studied to establish a composite reference
standard (see also section statistical analysis). The 18F-FDG PET/CT will be
analyzed by the nuclear medicine specialist working on duty as part of the
standard clinical routine.

Benefits
At this point, it is unknown whether the 18F-PSMA PET/CT detects MTC tumor
lesions. It is possible that the 18F-PSMA PET/CT detects (an) MTC lesion(s) not
detected by routine clinical imaging with CT, MRI and/or other PET scans.
However, as this is a feasibility study, the possible detection of new lesions
will not lead to diagnostic or treatment consequences. Participation in this
study will therefore not directly benefit the included patients.

Radiation burden and risks
Since patients undergo an extra PET scan (the 18F-PSMA PET/CT) when
participating in this study, there is an additional radiation burden to the
patient. The 18F-PSMA PET/CT implements a radiation burden of 3.9 mSv. There
are no known adverse events from intravenous injection of 18F-PSMA. As patients
require an intravenous line for administration of the tracer, there is a small
risk of adverse events related to this (i.e. hematoma, accidental subcutaneous
injection).

Time investment:
Patients are required to invest time in this study in the form of an extra
hospital visit. The whole procedure is expected to take maximum 3 hours total
(excluding travel time).

Incidental uptake in the prostate gland: if incidental uptake of PSMA is seen
in the prostate gland in male participants, the patient will be referred to the
urologist for an assessment.