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.
