European Nuclear Medicine Guide
Somatostatin receptor (SST) agonists[140], labelled with[68Ga] and [64Cu] [141-145]:
[68Ga]Ga-DOTA0-Tyr3octreotide ([68Ga]Ga-DOTA-TOC)_EMA 2016 and FDA 2019
[68Ga]Ga-DOTA0-Tyr3octreotate ([68Ga]Ga-DOTA-TATE)_FDA 2016
[64Cu]Cu-DOTATATE_FDA 2020
[68Ga]Ga-DOTA0-1NaI3octreotide ([68Ga]Ga-DOTA-NOC)_ European Pharmacopoeia 11.3 2024
Other SST-agonists approved locally at national level: e.g. [18F]AIF-NOTA-Octreotride in Belgium (2024)
Although all bind to SST2, different affinity profiles for other SST-subtypes were described [7-9]: DOTA-TATE has high affinity for SST2 but virtually no affinity for SST3 and SST5; DOT-ANOC exhibits good affinity also for SST3 and SST5, while DOTA-TOC binds also to SST5, although with lower affinity than DOTA-NOC. All agonists radiopharmaceuticals are considered clinically equivalent, however, caution is warranted in situations where differences could impact dosimetry or therapeutic decision-making. When images are visually assessed, semiquantitative parameters (either absolute or derived) are not directly comparable if different radiopharmaceuticals are employed
The primary indication is imaging well differentiated, SST-expressing neuroendocrine tumours(e.g. gastro-entero-pancreatic NET, pulmonary NET, paraganglioma, meningioma), both functioning and non-functioning, for:
initial staging (localize primary tumour and detect sites of metastatic disease, especially before surgery);
detection of the unknown primary tumour site in patients with known secondary neuroendocrine lesions;
restaging (to detect residual, recurrent or progressive disease), including a post-PRRT course assessment (3 to 12 months after the last PRRT-cycle)
assessing SST expression status, both visually as well as using semi-quantitative parameters (like SUV), to select eligible patients for SST- radionuclide therapy (PRRT) with ]s either the approved [177Lu]DOTA-TATE or other therapeutic beta (e.g. 90Y or 177Lu) or alpha (e.g. 225Ac, 212Pb) labelled experimental radiopharmaceuticals obtaining prognostic data (patient with lesions showing higher Gallium-68 somatostatin analogues uptake generally present a better prognosis).
Limited data is available on the clinical utility of employing SST PET/CT in SST-expressing non-neuroendocrine disorders.
Pregnancy (suspected or confirmed)
Breastfeeding (relative contraindication): if radiopharmaceutical administration is considered necessary, breastfeeding should be interrupted for approximately 4-24 hrs
Literature data indicate that SST analogues PET/CT imaging has good diagnostic performance for the evaluation of NET, better than SSTR scintigraphy and generally superior to CT/MRI for detecting disease extent. A large meta-analysis including a total of 2,105 well differentiated NET patients, reported a pooled sensitivity of 93% (95% CI 91-94%) and specificity 96% (95% CI95-98%). The area under the summary ROC curve was 0.98 (95% CI 0.95-1.0) [149]. Image reading has a good interobserver agreement [150]. Overall, PET/CT is safe and influences management in a large proportion of patients [151].
All radiopharmaceuticals are administered intravenously [141-147]
[68Ga]Ga-DOTA-TOC (uptake time: 55-90min):
-adult patients: 148[111-185]MBq (4 [3-5]mCi) based on FDA or 100-200MBq (2.7-5.4mCi) based on EMA prescribing information
-pediatric patients: 1.59MBq/Kg (0.043mCi/kg [0.3-3])
[68Ga]Ga -DOTA-TATE (uptake time 40-90min): 2MBq/Kg (0.054mCi/Kg) up to 200MBq (5.4mCi), based on prescribing information
[64Cu]Cu-DOTA-TATE (uptake time: 45-90min): 148MBq (4mCi), based on prescribing information
[68Ga]Ga-DOTA-NOC (uptake time: 60-90min): 100-200MBq_ European Pharmacopoeia 11.3 01/2024
Administered activities need to be adjusted to local camera performance and reconstruction methods (e.g. LAFOV systems allow lower injected activity and acquisition times).
No recommendations are given for paediatric nuclear medicine except for [68Ga]Ga-DOTA-TOC. It is suggested to follow the EANM pediatric dose calculator
Variation of injected activity may be caused by the short half-life of Gallium-68 and variable elution efficiencies obtained during the lifetime of the Germanium-68/Gallium-68 radionuclide generator. Flushing of the administration syringe with at least 10 mL of normal saline (NaCl 0.9%) and subsequent emptying into the i.v. access is recommended to maximize use of dispensed activity.
The effective dose for [68Ga]Ga -DOTA-TATE is 23 µSv/MBq. The organ with the highest absorbed dose is the spleen: 250 µGy/MBq. The total ED for [68Ga]Ga -DOTA-TOC (21 µSv/MBq) is slightly higher than that reported for 68Ga-DOTA-NOC, 17 µSv/MBq [152,153].
The range in effective dose for [68Ga]Ga -DOTA-TATE is: 2.3-4.6 mSv per procedure. [411].
The radiation exposure related to a CT scan carried out as part of a [68Ga]Ga -DOTA-octreotate 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."
Uptake outside the physiologic biodistribution sites is considered pathologic. When describing a pathologic known/suspected NET lesion, it is relevant to indicate if the uptake exceeds the one of the reference backgrounds (liver, spleen) in order to grade SST-expression (e.g. modified from PET Krenning score is based on the lesion with the highest SST uptake: 0, no uptake; 1, very low uptake; 2, uptake less than or equal to that of the liver; 3, uptake greater than the liver; and 4, uptake greater than that of the spleen) [154]. In case of dishomogeneous uptake within an otherwise CT-evident lesion, additional FDG imaging is indicated [155]. A still open issue is the validation of PET-based criteria to assess response to therapy [156].
Physiological biodistribution: pituitary gland, spleen (including accessory spleens), liver, adrenal glands, head of the pancreas, thyroid (very mild uptake) and the urinary tract (kidneys and urinary bladder).
False positive findings: activated lymphocytes (inflammation/infection), accessory spleen, pancreatic uncinated process, SST-expressing non-neuroendocrine tumours (anecdotal expression have been reported in breast carcinoma , melanoma, lymphoma, prostate carcinoma, non-small cell lung cancer, head and neck cancer, sarcoma, renal cell carcinoma, differentiated thyroid carcinoma, astrocytoma).
False negative findings: small lesions dimension (<5 mm) and tumours with low or variable expression of SST (e.g. medullary thyroid carcinoma, neuroblastoma, insulinoma, high grade NEN). Pheochromocytoma,or paraganglioma may show low or heterogeneous uptake.
No special preparation is required.
The issue of whether it is appropriate to discontinue SST analogue therapy before PET/CT is still under debate. Some authors suggested withdrawal (to avoid potential SST receptor blockade), while others have reported improved tumour/non-tumour ratio following pre-treatment with somatostatin analogues. Moreover, in some patients, therapy withdrawal might not be tolerated.
It is recommended to image a whole-body from skull base to mid-thigh, start 40–90 min after injection. Detailed recommendations regarding Gallium-68 somatostatin analogues PET/CT imaging are available in the EANM Guidelines.