European Nuclear Medicine Guide
3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine also known as:
[18F]FDOPA
FDOPA
[18F]FDOPA is a radiolabelled analogue of L-3,4-dihydroxyphenylalanine. For intracellular transport, [18F]FDOPA is a substrate for the L-system amino acid transporters like Large Aminoacid Transporters (LAT1 and LAT2).
The pathophysiological rationale for PET imaging of gliomas with [18F]FDOPA is increased amino acid transport in brain tumour cells resulting from overexpression of the transporter systems LAT1 and LAT2, which are related to alterations in the tumour vasculature and tumour cell proliferation.
The pathophysiological rationale for PET imaging of neuroendocrine neoplasias (NEN) with [18F]FDOPA is the ability of several types of NEN to take up, decarboxylate, and store amino acids such as DOPA and their biogenic amines [157]. [18F]FDOPA uptake is frequently observed in NEN with serotonin secretion [158.159].
[18F]FDOPA is indicated for use with PET in adults and paediatric population.
The following indications in oncology and endocrinology, have been particularly documented (according to the summary of product characteristics of [18F]FDOPA in various EU countries):
· Diagnosis:
Diagnosis and localisation of hyperplasia of β islet cells of the pancreas in the case of hyperinsulinism in infants and children;
Diagnosis and localisation of paraganglioma in patients with a gene mutation of the succinate dehydrogenase D variant;
Localisation of pheochromocytoma and paraganglioma.
Staging:
Pheochromocytoma and paraganglioma;
Welldifferentiated NEN of the midgut (jejunum, ileum, ileo caecal valve, appendix and ascending colon);
Detection in case of reasonable suspicion of recurrences or residual disease;
Gliomas of all grades of differentiation;
Pheochromocytoma and paraganglioma;
Medullary thyroid cancer with elevated serum levels of calcitonin;
Well differentiated NEN of the midgut;
Other digestive NEN when somatostatin receptor PET (or scintigraphy SRS) is negative.
Other indications in oncology are gathering evidence.
Characterisation: localization of the unknown primary tumour of a NEN diagnosed on a metastasis (so called CUP-NET), particularly in the case of mesenteric retractile adenopathy, high levels of 5 hydroxyindolacetic acid, or serotonin production by the lesion [158,159].
Neuroblastoma: staging, prognosis, and detection of recurrence [160,161]. Comparative studies are difficult to gather in this rare disease in children. A metanalysis compared seven different modalities [162] and found that [18F]FDOPA PET/CT exhibited the best diagnostic performance in the comprehensive detection of primary tumour and metastases for neuroblastic tumours, followed by [68Ga]-somatostatin analogues. There is a complementary between results of PET with [18F]FDOPA and with a somatostatin analogue (e.g. [68Ga]-DOTA-TOC) for evaluating tumour extension, and with [18F]-fluorodeoxyglucose (FDG) as a marker of aggressiveness [163, 164].
[18F]FDOPA is also indicated in Neurology for detecting loss of functional dopaminergic neuron terminals in the striatum, refer to chapter 3.2 of this Guide and/or to the corresponding EANM & SNMMI Guideline [165].
Pregnancy is considered in several countries as a contra-indication, although the dose to the foetus would be far below the known threshold for non-stochastic effects such as malformations. In very selected cases, a multidisciplinary discussion of the clinical case is mandatory in search for alternative imaging modalities without radiation exposure or postponing PET/CT after delivery.
When [18F]FDOPA PET/CT is performed in a lactating mother, breastfeeding should be suspended for 12 h, and the milk drawn after [18F]FDOPA injection should be discarded.
Close contact with children should be avoided for 12h after injection.
As rare cases of carcinoid symptoms have been reported after a bolus injection, injection should be slow over 1 min.
[18F]FDOPA was not mentioned in the 2006 EANM Guideline on PET imaging of gliomas [166]; at that time, its results were limited albeit promising [167].
Currently, [18F]FDOPA is considered as one of the most effective PET tracers for imaging gliomas together with [11C]-methionine and [18F]-fluoroethylthyrosine (FET). They are all transported across the blood–brain barrier and into cells by system L amino acid transport, they can all be expected to have similar pitfalls [168]
Two more recent Guidelines endorsed bv EANM, in adults [168] and in children [169] gathered extensive information concerning practice and clinical utility of [18F]FDOPA and of those two alternative tracers in the context of glioma.
For detection of extension of newly diagnosed gliomas, [18F]FDOPA is more sensitive for grading than [18F]FDG and diffusion weighted MRI [170,171].
[18F]FDOPA may identify gliomas missed on MRI [172] with a major impact on management in this setting (75% according to [173]).
More recently, it has been reported that [18F]FDOPA uptake is higher in case of isocitrate dehydrogenase (IDH) mutation [174], although this result has been challenged [175].
[18F]FDOPA is more sensitive than [18F]FDG in case of suspicion of recurrences or residual disease and in low grade as well as in high-grade cerebral tumours [176].
A meta-analysis of 15 articles concluded that [18F]FET and [18F]FDOPA have greater diagnostic value for glioma recurrence relative to [18F]FDG, [11C]-methionine and MRI [177].
[18F]FDOPA resulted in change in patients’ management in suspected recurrent glioma, with reported rates of 41% [178], or 23 % [179].
Quantification permits ruling out false positive results related to suspicious low uptake in post radiotherapy necrotic areas [180]. Static [18F]FDOPA PET images have a high accuracy for differentiating progression from treatment-related changes in a homogeneous population of high-grade gliomas with a reported added value of dynamic acquisitions (from 0 to 30 min post-injection) on the diagnostic and prognostic values in case of IDH-mutant high-grade gliomas [181,182].
Concerning the impact of [18F]FDOPA PET, its result changed the diagnosis and treatment plan in 33% of 12 patients with a suspicion of recurrent glioblastoma. In patients evaluated to assess residual glioblastoma infiltration after treatment (n = 53), [18F]FDOPA PET data had a lower impact with only 6% (3/53) of diagnostic changes and 4% (2/53) of therapeutic plan changes [183].
An EANM Guideline has been issued in 2017, addressing the performance of PET with [18F]FDOPA vs.[68Ga]somatostatin analogues in the detection of several types of NEN [184].
[18F]FDOPA PET is very useful for selecting those infants for surgery in case of [18F]FDOPA focal uptake rather than diffuse pancreatic uptake [185]. In case of focal uptake it shortens the intervention by guiding the surgical exploration of the pancreas.
The detection rate of focal [18F]FDOPA appeared significantly higher in patients with ABCC8 paternal monoallelic recessive gene mutation [186].
Two meta-analyses reported [18F]FDOPA exploration of congenital hyperinsulinism in infants. The pooled sensitivity and specificity of [18F]FDOPA PET in differentiating between focal and diffuse congenital hyperinsulinism (CHI) were 89% and 98%, respectively [187]. [18F]FDOPA PET was shown to be superior in distinguishing focal from diffuse CHI compared to pancreatic venous sampling and selective pancreatic arterial calcium stimulation with hepatic venous sampling. It localized focal CHI in the pancreas more accurately than pancreatic venous sampling and selective pancreatic arterial calcium stimulation with hepatic venous sampling, with a pooled accuracy 82% versus 76% and 64%, respectively [188]. In this setting, [18F]FDOPA PET is currently recommended by pediatric surgeons [189].
However, a newer PET tracer has recently emerged, a radioligand of the GLP1 receptor, potentially more specific than the metabolic tracer [18F]FDOPA to detect hyperfunctioning beta-cells in the pancreas. In a pilot study aiming to detect focal CHI, [68Ga]-NODAGA-exendin-4 PET/CT has higher clinical sensitivity and better interobserver reproducibility than [18F]FDOPA PET/CT, yielding images of better contrast [190].
The interpretation of [18F]FDOPA PET/CT in adult patients with hyperinsulinemic hypoglycemia can be difficult, since there are few differences between pathologic or non-pathologic areas of the pancreas, which show a very variable physiologic uptake of the tracer. Premedication with carbidopa (a peripheral AADC inhibitor) is disputed, as it decreases the overall pancreas uptake and the lesion-to-background ratio. Disappearance of [18F]FDOPA pancreatic foci has been reported after premedication with carbidopa in patients with hyperinsulinemic hypoglycaemia [191].
Nevertheless, some teams are still considering carbidopa-assisted [18F]FDOPA PET/CT in this context, since it does not imply 68Ga labelled tracers. The conclusion of a short comparative study of [18F]FDOPA vs. [68Ga]-DOTATOC in 21 patients was “when [68Ga]-exendin-4 is not available, PET/CT with a 68Ga-somatostatin analogue should be the first choice for insulinoma functional imaging” [192].
In fact, [68Ga]-exendin-4 will probably become the reference PET tracer for detecting benign insulinomas, as illustrated in a multicentre trial. The accuracy of [68Ga]-exendin-4 PET/CT (94%) was greater than that of PET/CT with a [68Ga]-somatostatin analogue (65%) or [18F]FDOPA (33%), contrast-enhanced CT/contrast-enhanced diffusion-weighted imaging-MRI (83%), and invasive endoscopic ultrasound (83%). In 13% of patients, a correct diagnosis was only reached after exendin PET/CT [190].
An EANM & SNM Guideline has been issued in 2019 specifically about radionuclide imaging of phaeochromocytoma and paraganglioma [194].
The two most important factors associated with [18F]FDOPA positivity include the embryological origin (parasympathetic vs. sympathetic) of the phaeochromocytoma or paraganglioma and the succinate dehydrogenase (SDH)x mutation status of patients. One advantage of [18F]FDOPA PET/CT over [123I]MIBG scintigraphy and other radiopharmaceuticals is its limited uptake by normal adrenal glands [195]. As a consequence, the sensitivity of detection of 17 pheochromocytomas was reported as soon as 2002 to be 100% for [18F]FDOPA PET (without CT fusion) and of 71% for [123I]MIBG SPECT [196].
In patients with a gene mutation of the SDH subunit D [18F]FDOPA PET/CT has proven efficacy for diagnosis and localisation of paraganglioma, with pooled patient-based detection rate of around 90% [159,197,198]. SDHD mutation predisposes to the development of glomus tumours; in the series of Hoegerle et al., no glomus tumour was detected by MRI that was FDOPA-negative [199].
A meta-analysis of 11 studies comprising 275 patients with suspected paraganglioma irrespective of SDH mutation status found that the pooled sensitivity of [18F]FDOPA PET(/CT) in detecting paraganglioma was 91% (patient-based) and 79% (lesion-based) [200]. The pooled specificity of [18F]FDOPA PET(/CT) was 95% for both patient-based and lesion-based analyses.
With regard to metastatic disease, [18F]FDOPA PET/CT was found to perform better for SDHB-negative phaeochromocytoma or paraganglioma than for SDHB-positive phaeochromocytoma or paraganglioma (sensitivity: 93% vs. 20%, respectively) [201-206].
A more recent metanalysis of the results of 21 comparative studies concluded that [18F]FDOPA and 68Ga-somatostatin analogue PET are both sensitive for localizing paraganglioma. However, [18F]FDOPA is the most sensitive for detecting pheochromocytoma, while 68Ga-somatostatin analogue is superior to [18F]FDOPA for metastatic sympathetic and head-neck paraganglioma and SDHx-related paraganglioma [207,208].
Very high [18F]FDOPA PET/CT sensitivity values have been reported for the detection of phaeochromocytoma or paraganglioma associated with Von Hippel-Lindau syndrome, endothelial PAS domain protein 1/ hypoxia-inducible factor 2α and fumarate hydratase, which are often multiple and recurrent and occasionally exhibit a fairly high metastatic potential [209-211]. In a series of 52 patients with Von Hippel-Lindau syndrome, 15% of all pancreatic lesions and 30% of extra-pancreatic lesions were identified only by [18F]FDOPA PET and not by other imaging techniques [209].
In a prospective study, [18F]FDOPA PET influenced treatment decisions in 14/48=29% of patients [206].
A specific EANM Guideline on this topic has been published in 2020 [212].
At diagnosis and staging of MTC in 32 patients, [18F]FDOPA PET/ceCT obtained a sensitivity of 88% in the primary tumour (mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. Its sensitivities in the detection of central and lateral metastatic neck lymph nodes (LN) were 53% and 73%, greater than 20% and 39%, respectively, for neck ultrasonography [213]. At initial staging of 50 other MCT patients, sensitivities for tumour and metastatic LN detection were 86% and 57%, respectively for [18F]FDOPA PET/CT, vs. 92% and 43%, for US. Mediastinal LN or distant metastasis, were diagnosed only on PET/CT, both in 3/50=6% of patients [214].
Actually, data on clinical efficacy of [18F]FDOPA in localizing lesions of MTC have been obtained mostly in recurrent cases after thyroidectomy, prompted on rising serum levels of calcitonin and/or carcinoembryonic antigen (CEA). In this context of biochemical recurrence, imaging is recommended in case serum calcitonin >150 ng/mL [215]. According to Zhang et al. [216], the optimal cutoff values of basal calcitonin and CEA serum levels to obtain positive [18F]FDOPA PET/CT results were 64 ng/L, and 4 µg/L, respectively. Overall, in localizing lesions of MTC, the results of published studies confirm the superiority of [18F]FDOPA when compared with [18F]FDG or other radiopharmaceuticals and particularly for detecting metastatic LN [218-221]. To remove all millimetre-sized metastatic LN, a “compartment oriented” surgical approach has been recommended, when one LN is positive on [18F]FDOPA PET/CT [111]. According to a bibliographic survey in 2013, [18F]FDOPA was the best tracer for functional imaging of MTC [223], which holds true 7 years later: a meta-analysis of 14 direct comparison studies using 5 different PET radiopharmaceuticals concluded that [18F]FDOPA PET clearly showed a best performance for the detection of recurrent MTC in both patient- and lesion-based analyses regardless of serum calcitonin or CEA levels and calcitonin doubling time [224].
Negativity of [18F]FDOPA PET/CT in case of biochemical recurrence of MTC is correlated with a significantly longer progression-free survival [225]; nevertheless, [18F]FDG has been proposed as the next PET tracer. Compared with morphological imaging, [18F]FDOPA PET/CT has a clear advantage with regards to specificity [226,227].
Early image acquisition starting during the first 15 min [228,229] or even earlier [230] is advised. In case of negative [18F]FDOPA PET/CT (or PET/MRI),
Using [18F]FDOPA PET/CT as the first line functional imaging modality for the management of digestive NEN originating from midgut (jejunum, ileum, appendix, and right colon) allows detection of small lesions [231,232,233],and of NEN peritoneal carcinomatosis with very high performance [234].
The greatest impact of [18F]FDOPA PET on patient management was observed for carcinoid tumours (11/22=50%) and was clinically relevant in every case [235]. A non-negligible difference for detection of midgut NEN in favour of [18F]FDOPA PET/CT was observed in a meta-analysis: the pooled patient, site, and lesion-based sensitivity of [18F]FDOPA was 83%, 89% and 95%, respectively vs. 88%, 92% and 82% for PET with a somatostatin analogue [236].
In a 41 patient study focusing on metastatic spread of ileum NETs [237], [18F]FDOPA and [68Ga]-DOTATOC showed similar per-patient detection rates (97% for both). But, of a total of 605 positive lesions, 122 (20%) were detected exclusively by [18F]FDOPA PET/CT, 25 (4%) by [68Ga]-DOTATOC PET/CT only, and 458 (76%) by both modalities. In a per-lesion analysis, [18F]FDOPA PET/CT performed better than [68Ga]-DOTATOC PET/CT (overall detection rates of 96% vs 80%; P < .001), detecting significantly more metastases than [68Ga]-DOTATOC PET/CT in the liver, peritoneum, abdominal and supra-diaphragmatic LN.
In case of differentiated pancreatic NEN, PET with a somatostatin analogue is the most effective first line examination, except if Ki67 >10% favours [18F]FDG PET. If PET with a somatostatin analogue is unavailable (due to a lack of gallium-68 labelling capability) or negative, particularly in case of gastric or duodenal NEN [18F]FDOPA PET can be more effective in detecting non-functioning pancreatic NEN than SPECT/CT with a somatostatin analogue [238]. It can also be indicated in some cases of positive somatostatin receptor PET or [18F]FDG PET.
In occult NENs with negative conventional and SRS, [18F]FDOPA PET localised the primary tumour in 12/27=44%, especially well-differentiated and serotonin secreting NENs [158]. In another series of occult NEN, a 4/25=16% rate of impact on management was reported, clinically relevant in 3/4 [234]. In case of equivocal origin of a positive focus, [18F]FDOPA has the advantage to be more tumour-specific than the somatostatin analogues or [18F]FDG which are taken-up by leucocytes in inflammatory lesions. If the primary tumour is [18F]FDOPA-positive and a questioned focus is [18F]FDOPA-negative, a non-NEN nature is probable.
Carcinoid heart disease occurs in patients with serotonin-producing NENs, which take-up [18F]FDOPA. The prevalence of cardiac metastases detected with [18F]FDOPA PET/CT in a series of 116 patients was 13%. There appears to be no relationship between the presence of cardiac metastases and transthoracic echocardiography parameters of carcinoid heart disease [239].
In a retrospective survey, 4/149 patients presented at least 1 orbital focus of increased [18F]FDOPA uptake, all of them presented a metastatic small intestine NEN. [68Ga]-DOTATOC PET/CT was positive, supporting the hypothesis of genuine metastases [240].
The suggested activities of [18F]FDOPA to administer are 4 MBq/kg of body mass, 50-400 MBq.
As rare cases of carcinoid symptoms have been reported after a bolus injection, injection should be slow over 1 min.
The effective dose for [18F]FDOPA is 25 µSv/MBq [241]. The organ with the highest absorbed dose is the urinary bladder wall: 300 µGy/MBq. [241]
The range in effective dose for [18F]FDOPA is 1.3-10 mSv per procedure.
The radiation exposure related to a CT scan carried out as part of an [18F]FDOPA PET/CT study depends on the intended use of the CT study and may differ from patient to patient.
Caveat:
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
False-positive results of [18F]FDOPA PET in inflammatory lesions have been very rarely reported. Nevertheless, the possibility of an inflammatory lesion should be kept in mind, when an unexpected [18F]FDOPA focus is detected. The physiologic biodistribution must be taken into account in the interpretation. In particular, uptake in the basal ganglia, diffuse uptake in the pancreas, uptake in the gallbladder leading to subsequent activity in the gut, and uptake in the kidney leading to “hot spots” aspect in the ureters and a high activity in the bladder should be considered in the interpretation.
It is recommended that [18F]FDOPA should be injected in patients fasting for a minimum of 4 h without limiting water intake to avoid a potential interference with the digestive intake of amino acids.
In order to obtain images of the best quality and to reduce the radiation exposure of the bladder, patients should be encouraged to drink sufficient amounts and to empty their bladder prior to and after the PET examination.
The administration of 100 to 200 mg of carbidopa one to one and a half hours before the injection of [18F]FDOPA may be recommended for neurological indications, but is disputed for oncological indications.
The field of view of functional imaging with [18F]FDOPA should be adapted to the diagnostic target:
Dedicated brain imaging in case of gliomas;
Acquisition from the top of the head to mid-thigh in other oncological indications;
Imaging of abdominal region in case of hyperinsulinism in infants.
Early image acquisition (around 10 min post-injection) increases NEN detection in case of medullary thyroid cancer [228, 229].
In PET/CT studies, attenuation correction and scatter correction are performed using the CT transmission data. A PET/CT examination can include different types of CT scan depending on the CT characteristics, the accepted radiation exposure, and the use (or not) of oral and/or intravenous contrast agents:
Low-dose CT: CT scan that is performed only for attenuation correction of PET images and anatomical correlation of PET findings (with reduced voltage and/or current of the X-ray tube settings), i.e., a low-dose CT is, a priori, not intended for a dedicated radiological interpretation.
Diagnostic CT: CT scan with or without intravenous and/or oral contrast agents (ceCT) and commonly using higher X-ray doses than low-dose scans. Diagnostic CT should be performed according to applicable local or national protocols and guidelines.