FDOPA

10.7.1 Radiopharmaceutical:

• 3,4-dihydroxy-6-[¹⁸F]fluoro-L-phenylalanine also known as:
  • [¹⁸F]FDOPA
  • FDOPA

10.7.2 Uptake mechanism / biology of the tracer

[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 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 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 [270,271]. [¹⁸F]FDOPA uptake is observed much more frequently in NEN with serotonin secretion (126).

10.7.3 Indications

[¹⁸F]FDOPA is indicated for use with PET in adults and paediatric population.

The following indications have been particularly documented (according to the summary of product characteristics of [¹⁸F]FDOPA in various EU countries):

• Diagnosis:
  • Diagnosis and localization of hyperplasia of β islet cells of pancreas in the case of hyperinsulinism in infants and children;
  • Diagnosis and localization of paraganglioma in patients with a gene mutation of the succinate dehydrogenase D variant;
  • Localization of pheochromocytoma and paraganglioma.

• Staging:
  • Pheochromocytoma and paraganglioma;
  • Well differentiated 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 is negative.

Other indications in oncology are gathering evidence and may be considered as documented:

• Diagnosis: 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 [272,273].
• Neuroblastoma: staging, prognosis, and detection of recurrence [274–277].

10.7.4 Contra-indications

• 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 comprehensive discussion of the clinical case is mandatory in search for imaging modalities without radiation exposure or postponing PET/CT after delivery.
• When [¹⁸F]FDOPA PET/CT is performed in a lactating mother, breast feeding 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.
• Injection should be slow over 1 min. Rare cases of carcinoid symptoms have been reported after a bolus injection.

10.7.5 Clinical performances

In gliomas:

• For detection of extension of newly diagnosed gliomas, [¹⁸F]FDOPA is more sensitive than [¹⁸F] FDG or [¹⁸F] FLT and more sensitive than diffusion weighted MRI for grading [278,279]. In a minority of cases, [¹⁸F]FDOPA might identify gliomas missed on MRI [280].
• [¹⁸F]FDOPA is more sensitive than FDG and FLT in case of reasonable suspicion of recurrences or residual disease and in low grade as well as in high grade cerebral tumours [278].
• Quantification permits ruling out false positive results related to suspicious low uptake in post radiotherapy necrotic areas [281].
• [¹⁸F]FDOPA resulted in 41% change in patients’ management in suspected recurrent glioma [282].

In hyperinsulinism in infants:

• [¹⁸F]FDOPA PET(/CT) is very useful for selecting those infants for surgery in case of [¹⁸F]FDOPA focal uptake rather than diffuse pancreatic uptake, and it shortens the intervention by guiding the surgical exploration of the pancreas.
• Two meta-analyses reported [¹⁸F]FDOPA exploration of congenital hyperinsulinism in infants. The pooled sensitivity and specificity of [¹⁸F]FDOPA PET (CT) in differentiating between focal and diffuse congenital hyperinsulinism were 89% and 98%, respectively [283]. [¹⁸F]FDOPA PET was shown superior in distinguishing focal from diffuse congenital hyperinsulinism compared to pancreatic venous sampling and selective pancreatic arterial calcium stimulation with hepatic venous sampling. It localized focal congenital hyperinsulinism in the pancreas more accurately than pancreatic venous sampling and selective pancreatic arterial calcium stimulation with hepatic venous sampling, pooled accuracy 82% versus 76% and 64%, respectively [284].

In detection, localization and (re)staging in case of reasonable suspicion of recurrence or residual disease of pheochromocytoma or paraganglioma:

• In patients with a gene mutation of the succinate dehydrogenase (SDH) subunit D, the pooled patient-based detection rate for diagnosis and localization of paraganglioma was 91% [273]. In a study which included patients with hereditary paraganglioma syndromes with a SDH mutation, [¹⁸F]FDOPA detected paraganglioma and/or NEN in 13/15 patients with SDHD mutation and 1/5 with SDHB mutation [285]. Thus, [¹⁸F]FDOPA PET/CT screening of phenotypically healthy patients carrying a SDHx germline mutation appears to be highly recommended and might also play a role in long term follow-up. In patients with SDHB mutation the results are discrepant. In one study, FDG had a higher overall lesion-based sensitivity (83%) than [¹⁸F]FDOPA (20%), but in a separate study, [¹⁸F]FDOPA detected lesions in all 3 patients, whereas the only patients whose tumours were not imaged on [¹⁸F]FDG PET/CT were two SDHB patients [286,287].
• A meta-analysis of 11 studies comprising 275 patients with suspected paraganglioma irrespective of SDH status found that pooled sensitivity of [¹⁸F]FDOPA PET(/CT) in detecting paraganglioma was 91% (patient-based) and 79% (lesion-based) [288]. The pooled specificity of [¹⁸F]FDOPA PET(/CT) was 95% for both patient-based and lesion-based analyses. [¹⁸F]FDOPA PET(/CT) seems to be accurate in both adrenal or extra-adrenal, sympathetic or parasympathetic, functioning or non-functioning, and metastatic or non-metastatic paraganglioma or Von Hippel-Lindau syndrome [286,289–300].
• However, two recent comparative studies conducted in a limited number of patients reported a trend for better lesion-based sensitivity with ⁶⁸Ga-DOTATATE, a ligand for somatostatin receptor PET, than with [¹⁸F]FDOPA in detecting lesions of head and neck paraganglioma especially in cases of SDHD mutation [301].
• Concerning the impact of [¹⁸F]FDOPA PET on therapeutic management of paraganglioma patients, the rate of change in patient management was 12% overall (3/24) and 20% (3/15) in proven pheochromocytoma which led to pertinent treatment decisions [302]. In a prospective study, [¹⁸F]FDOPA PET influenced treatment decisions in 29% of patients (14/48) [300]. 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 [292].

In medullary thyroid cancer (MTC):

• Data on clinical efficacy of [¹⁸F]FDOPA in localizing lesions of medullary thyroid cancer have been obtained mostly in cases of rising serum levels of calcitonin and/or carcinoembryonic antigen after thyroidectomy. In this context, imaging is recommended if calcitonin >150 ng/mL [303]. However, no precise figure for a threshold in calcitonin serum levels for performing [¹⁸F]FDOPA PET/CT can be recommended at the moment, since detection of lesions is being reported at increasingly lower calcitonin levels due to continuing improvement in PET/CT (MRI) cameras [296,304–306]. Overall, in localizing lesions of medullary thyroid cancer, the results of published studies confirm the superiority of [¹⁸F]FDOPA when compared with [¹⁸F]FDG or other radiopharmaceuticals and particularly for detecting metastatic lymph nodes [293,296,304,306–312]. To remove all millimetre-sized metastatic lymph nodes, a “compartment oriented” surgical approach has been recently recommended, when one lymph nodes is positive on [¹⁸F]FDOPA PET/CT [313].
• Thus, according to a bibliographic survey, [¹⁸F]FDOPA is currently the best tracer for functional imaging of medullary thyroid cancer; early image acquisition starting during the first 15 min is advised [314,315]. In case of negative [¹⁸F]FDOPA  PET/CT (MRI), [¹⁸F]FDG should be proposed as the next PET tracer.
• Compared with morphological imaging, FDOPA has a clear advantage with regards to specificity [293,305].

In well differentiated NEN of midgut origin:

• 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 [293,304,316,317].
• The pooled patient, site, and lesion-based sensitivity of [¹⁸F]FDOPA is 89%, 76%, and 97% [272,304,316–318].
• [¹⁸F]FDOPA imaging induced relevant changes in patient management in 50% of 22 patients with histologically documented NEN of the ileum, and the therapeutic decisions were relevant in all cases according to follow-up data (156). In a series of 16 patients with midgut NEN, [¹⁸F]FDOPA PET resulted in modification or even complete change in therapeutic strategy in 31% of the cases [293].
• In midgut NEN, the superiority of [¹⁸F]FDOPA over somatostatin receptor scintigraphy has been confirmed by several teams, however, robust comparative studies with somatostatin receptor PET are not yet available.

In other NEN:

• In case of differentiated pancreatic NEN, somatostatin receptor PET is the most effective first line examination, except, however, if Ki67 >10% favours [¹⁸F]FDG PET. If unavailable or negative, [¹⁸F]FDOPA PET/CT can be useful, particularly in case of gastric or duodenal NEN and also in some cases of positive somatostatin receptor PET or [¹⁸F]FDG PET. When there is doubt concerning the nature of a positive focus, [¹⁸F]FDOPA is 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 the questioned focus is [¹⁸F]FDOPA negative, a non-NEN nature is probable. If somatostatin receptor PET is unavailable (due to a lack of Gallium-68 labelling capability), [¹⁸F]FDOPA PET can be more effective in detecting non-functioning pancreatic NEN than somatostatin receptor SPECT/CT [319].

10.7.6 Activities to administer

The suggested activities to administer are:

• [¹⁸F]FDOPA: 4 MBq/kg ; 50-400 MBq

10.7.7 Dosimetry

The effective dose for [¹⁸F]FDOPA is 25 µSv/MBq [3]. The organ with the highest absorbed dose is the urinary bladder wall: 300 µGy/MBq.

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."

10.7.8 Interpretation criteria/major pitfalls

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.

10.7.9 Patient preparation

It is recommended that [¹⁸F]FDOPA should be injected in patients fasting for a minimum of 4 h without limiting water intake in order to avoid a potential interference with 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 is recommended for neurological indications but recommended less frequently for oncological indications.

10.7.10 Methods

No EANM guidelines are currently available.

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 (10 min) increases NEN detection in case of medullary thyroid cancer [315].

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 (CT-AC) 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 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.