European Nuclear Medicine Guide
On 26 June 2020, orphan designation EU/3/20/2295 was granted by the European Commission to Stichting Katholieke Universiteit, Netherlands, for Lys40(NODAGA-68Ga)NH2-exendin-4 for the diagnosis of insulinoma [325]. Since approximately one-third of insulinomas do not express somatostatin receptors (SST) [326], alternative target-specific radiopharmaceuticals were explored: exendin-4 has been used for functional imaging of benign insulinoma with both PET and SPECT and selectively binds to GLP-1R (glucagon-like peptide) on β pancreatic cells [327].
Insulinomas are the most common neuroendocrine neoplasms of the pancreas (incidence 1–4 cases per million people per year), sometimes as part of MEN1 (multiple endocrine neoplasia) [328,329]. Approximately 0.3 people in 10,000 are diagnosed with insulinoma in the European Union (EU) [325]. Benign insulinomas account for the vast majority (preferential surgical approach is pancreas preserving: enucleation or resection), while malignant insulinomas are estimated to account for about 6% of all insulinomas [330]. Clinical symptoms are highly heterogeneous at presentation: from episodes of hypoglycaemia to difficult-to-control hypoglycaemia-induced symptoms.
Precise pre-operative localization is essential to determine the anatomical relation to important structures such as the pancreatic duct or blood. Small lesion size (less than 1 cm in approximately half the cases) represents a challenge for imaging [326,331-333]: CT and MRI currently reach sensitivities of up to 70% and 90%, respectively [331]. The indication for [Ga]Ga-NODAGA exendin is imaging of GLP1-expressing benign insulinoma (especially at pre-operative level).
Pregnancy (suspected or confirmed)
Breastfeeding (relative contraindication): if radiopharmaceutical administration is considered necessary, breastfeeding should be interrupted for approximately 4 hrs and can be restarted when the radiation dose to the child would be lower than 1 mSv.
Heterogeneity of the radionuclide and chelator used, the technology used for imaging, and the small patient cohort make it difficult to derive definitive data on accuracy. However, although limited, preliminary data are encouraging regarding the advantages of exendin-4 PET/CT compared with the standard imaging modalities for imaging of GLP1-expressing insulinoma. A very recent report [334] indicated the superiority of exendin PET/CT in comparison to all current routine imaging modalities for pre-operative localization of benign insulinomas in a cohort of 69 patients with biochemically proven adult endogenous hyperinsulinemic hypoglycaemia: the accuracy of exendin PET/CT (94.4%; 95% CI, 84.6%–98.8%) was greater than that of SST PET/CT (64.8%; 95% CI, 50.6%–77.3%), contrast-enhanced CT/contrast-enhanced diffusion-weighted MRI (83.3%; 95% CI, 70.7%–92.1%), and endoscopic ultrasound (82.8%; 95% CI, 64.1%–94.1%); in 13% of patients, a correct diagnosis was only reached after exendin PET/CT.
Based on the literature data, a slow intravenous injection of 82.4 ± 14.9 MBq (range 43–106 MBq) 68Ga-DOTA-exendin-4 [335] and blood glucose monitoring (samples were taken 2, 5, 15, 30, 60, 120, and 180 min after injection) are recommended.
The mean total effective dose for adults was very low (0.71 ± 0.07 mSv for a standard injected activity of 100 MBq) [336]. The organ with the highest absorbed dose was the kidney (47.3 ± 10.2 mGy/100 MBq). The estimated effective dose was 2.32 ± 0.32 mSv for an injected activity of 20 MBq in newborns. This dose decreased to 0.77 ± 0.11 mSv/20 MBq for 1-year-old children and 0.59 ± 0.05 mSv for an injected activity of 30 MBq in 5-year-old children.
Uptake outside the physiological biodistribution sites is considered pathological. Physiological distribution with moderate uptake in the salivary glands, diffuse uptake in the pancreas, and renal radiotracer excretion through the kidneys with subsequent accumulation in the bladder [337].
False positive: nesidioblastosis, Brunner’s gland physiological uptake/hyperplasia, insulinoma overlap with the kidneys.
False negative: small lesions (<1cm), low target expression.
Image acquisition after 30–60 minutes post-injection; Typically 10 minutes per bed position over the abdomen in focused imaging. For whole-body or larger coverage, additional bed positions with shorter durations may be used [413].