BACKGROUND AND RATIONALE.6-[18F]fluoro-dihydroxyphenylalanine (18F-DOPA) is a large neutral amino acid that
resembles natural L-3.4-dihydroxyphenylalanine (L-DOPA) biochemically. L-DOPA is a
precursor for dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline),
collectively known as catecholamines. 18F-DOPA enters the biochemical pathway of L-DOPA
both in the brain and peripherally, and can be imaged with a positron emission tomography
/ computed tomography (PET/CT) scanner. 18F-DOPA can therefore allow imaging of the
L-DOPA metabolic pathway with a high target-to-background ratio providing valuable
information for a number of diseases.
While 18F-DOPA is an established diagnostic tracer at a number of different institutions
globally, given the short half-life of 18F (110 minutes) this tracer cannot be imported
for local use. The Edmonton PET Centre has recently developed a production method for
this tracer allowing local access. An initial study at the University of Alberta
(Pro00055342) has demonstrated this tracer to have an acceptable safety profile, an
expected biodistribution (both physiologic and disease-related), and has established
clinical efficacy of the tracer.
In March, 2020 the University of Alberta Hospital (UAH) installed a new PET/CT scanner
(GE Discovery MI) with a digital detector system and new iterative image reconstruction
algorithms that represent a substantial technological improvement compared to the
previously installed scanner. It is expected that this new system will reduce artifact
and will increase the sensitivity for the detection of smaller lesions.
Our initial study demonstrated rapid urinary excretion with intense collection of
activity within the urinary bladder. While this physiology was expected, it did result in
diminished image quality in the evaluation of the pelvis in some patients. Improved image
reconstruction algorithms available on the new GE Discovery MI PET/CT system may improve
imaged quality related to this problem. Based on our experience with
18F-fluorodeoxyglucose (FDG) PET/CT scans, the administration of intravenous furosemide
prior to imaging can also substantially improve the image quality in the pelvis. These
potential improvements have not yet been established with 18F-DOPA.
A second observation from our initial study was that many participants demonstrated
intense early activity at the gallbladder fundus. While biliary and gallbladder activity
are described in the normal biodistribution of 18F-DOPA, the observed distribution
suggests that the gallbladder fundus activity reflects primary uptake rather than reflux
of activity within bile into the gallbladder.
The rationale for this study is to explore the efficacy of these optimization parameters
(new digital PET/CT camera system and use of intravenous furosemide) in the context of
18F-DOPA PET/CT imaging for patients with clinical indications for the scan. Imaging data
from this study will be compared with data from the prior study (Pro00055342) to
determine if the new digital detector PET/CT technology and preparatory furosemide
administration improves image quality for these patients.
A subgroup will also be scanned dynamically at the abdomen to better assess the pattern
of gallbladder activity over time. This will include a mixture of clinical indications
listed within the inclusion criteria. All patients will be screened for a history of
previous gallbladder disease at the time of the scan by questionnaire. The intention of
this sub-study is to better determine 18F-DOPA activity patterns associated with the
gallbladder and to explore if there is a correlation between dopaminergic degeneration in
the brain and the gallbladder.
PURPOSE AND STUDY OBJECTIVE:
Trial Type: Phase III non-randomized, non-blinded prospective cohort clinical trial of
patients with a clinical indication for 18F-DOPA PET/CT imaging.
The primary purpose of this study is to assess optimization parameters for 18F-DOPA PET
CT imaging at UAH including the impact of new digital detector PET/CT technology as well
as the impact of preparatory intravenous furosemide administration on image quality
within the pelvis. A secondary purpose of this study is to better delineate the pattern
of 18F-DOPA activity associated with the gallbladder and to explore if there is a
relationship between dopaminergic denervation in the gallbladder and the brain.
Only patient populations for which there are established clinical indications for the use
of 18F-DOPA will be included in this study. Participation in this study will allow access
to this tracer for patients in Alberta as there is no Health Canada approved similar
tracer currently available. 18F-DOPA is an established clinical tracer at multiple
institutions globally and has been approved for clinical use at multiple European centres
for many (10+) years. Established clinical indications in the literature include:
1. Pediatric patients (less than 18 years old) with congenital hyperinsulinism. The
18F-DOPA scan is used to plan required surgical intervention for these patients.
2. Pediatric patients (less than 18 years old) with neuroblastoma. The 18F-DOPA scan is
indicated for pre-operative assessment of a mass suspected to be a neuroblastoma,
staging, re-staging, and assessment of recurrence in this patient group.
3. Pediatric (less than 18 years old) or Adult patients (18 or older) with known or
clinically suspected neuroendocrine tumor. These include patients with carcinoid
tumor, pheochromocytoma, paraganglioma, and medullary thyroid cancer. 18F-DOPA is
indicated for metabolic assessment of a mass suspected to represent one of these
tumor-types, for staging of a known tumor, for re-staging, and for assessment of
recurrence in this patient group.
4. Adult patients (18 or older) with a clinical suspicion of Parkinson's disease or
Lewy body dementia. 18F-DOPA is indicated to differentiate benign essential tremor
from Parkinson's disease in this patient group [22-26]. 18F-DOPA may also be used to
differentiate Lewy body dementia from other dementia types.
5. Pediatric (less than 18 years old) or Adult patients (18 or older) with brain tumors
(primary or metastatic). 18F-DOPA is indicated for biopsy planning, radiation
therapy planning, and post-therapy assessment to differentiate residual viable tumor
from post-therapy necrosis in this patient population.
When requested for patients falling into one of these diagnostic groups, an 18F-DOPA
PET/CT scan will be performed and interpreted clinically with the results conveyed to the
referring physician.
Image optimization (the primary study objective) will be evaluated based on the
following:
- - For patients with abnormal activity, the smallest 3 lesions will be recorded in
terms of size (mm) and activity (SUVmax).
For PET-avid lesions, the size measurement
will be based on measuring the maximum dimension of the corresponding lesion on the
CT scan component if possible. If not possible, a size measurement based on the PET
images will be used. The minimum lesion size and average (3 smallest lesions) will
be compared with a cohort of scans acquired on the previous non-digital PET/CT
scanner (retrospective cohort of 50 positive patients, Pro00055342).
- - The SUVmax, SUVmean, and SUV standard deviation of urinary bladder activity will be
measured and compared to a retrospective cohort of 50 patients from a previous study
(Pro00055342)
- A subjective score will be applied to the pelvis with respect to image artifact
related to bladder activity (0 = no artifact, 1 = mild artifact, 2 = severe
artifact).
This will be compared to scoring of the previous study (retrospective
cohort of 50 patients, Pro00055342) retrospectively.
Gallbladder activity pattern (the secondary objective) will be evaluated based on the
following:
- - SUVmax measurements of the gallbladder fundus, gallbladder neck, common bile duct,
right and left main intrahepatic ducts, and liver parenchyma (right and left lobes,
3 cm diameter VOI) will be measured at 5 minute increments.
These will be analyzed
in total, and subgroups will be compared (32 PD vs.#46; 32 non-PD participants).
- - All participants will be screened by questionnaire at the time of the scan as to
whether there is a history of previous gallbladder disease.
The positive response
rate will be compared between three groups: non-PD patients, PD patients with
objective evidence of dopaminergic denervation (positive FDOPA scan), PD patients
without objective evidence of dopaminergic denervation (negative FDOPA scan).
PATIENT POPULATION:
A total of 800 patients who meet the inclusion criteria will be identified based on
referrals from physicians who deem the imaging studies potentially useful for clinical
care. It is anticipated that complete enrollment will take 5 years (approximately 160
scans per year).
Sample size calculation is based on the following. There will typically be 5 participants
total scanned per day. Dynamic imaging will be restricted to one patient per scanning day
due to time constraints related to the scanner, as this requires the participant to lie
quietly in the PET/CT scanner for up to one hour. Allowing for this restriction, it is
estimated that the overall participation rate for dynamic scanning will be 10%. Based on
a minimum total sample size of 64 participants for the secondary objective analysis, a
total minimum study population of 640 is required. Allowing for some potential buffer for
recruitment, a total of 800 participants is planned.
The minimum sample size of 64 participants is based on the following estimations:
gallbladder fundus SUVmax mean 10.9, SUVmax DS 4.6 (measured from cohort of 10 patients
from the previous study), α = 0.05, and power = 0.80. Two groups of 32 participants (64
total) should allow for detection of a minimum 30% difference in SUVmax involving the
gallbladder fundus between the two groups.
