68Gallium- Somatostatin Analogues

10.6.1 Radiopharmaceutical: Gallium-68 somatostatin analogues, including:

• [⁶⁸Ga]Ga-DOTA⁰-Tyr³octreotide ([⁶⁸Ga]Ga-DOTA-TOC)
• [⁶⁸Ga]Ga-DOTA⁰-1NaI³octreotide ([⁶⁸Ga]Ga-DOTA-NOC)
• [⁶⁸Ga]Ga-DOTA⁰-Tyr³octreotate ([⁶⁸Ga]Ga-DOTA-TATE)

10.6.2 Uptake mechanism / biology of the tracer

The somatostatin analogues [⁶⁸Ga]Ga-DOTA-TOC, [⁶⁸Ga]Ga-DOTA-NOC, and [⁶⁸Ga]Ga-DOTA-TATE bind with varying affinity to SSTR which are over-expressed on neuroendocrine tumour cells. Although [⁶⁸Ga]Ga-DOTA-TOC, [⁶⁸Ga]Ga-DOTA-NOC, and [⁶⁸Ga]Ga-DOTA-TATE can all bind to SSTR-2, they have different affinity profiles for other SSTR subtypes: [⁶⁸Ga]Ga-DOTA-NOC exhibits good affinity for SSTR-3 and SSTR-5, while [⁶⁸Ga]Ga-DOTA-TOC binds to SSTR-5, although with lower affinity than [⁶⁸Ga]Ga-DOTA-NOC. [⁶⁸Ga]Ga-DOTA-TATE has a predominant affinity for SSTR-2. However, these differences in SSTR binding affinity are not associated with significant clinical differences, although the SUV values are not directly comparable.

10.6.3 Indications

• The primary indication is imaging well differentiated, SSTR-expressing neuroendocrine neoplasms (e.g. gastro-entero-pancreatic NEN, pulmonary NEN, paraganglioma, meningioma), both functioning and non-functioning, for:
• initial staging (localize primary tumour and detect sites of metastatic disease);
• detection of the unknown primary tumour site in patients with known secondary neuroendocrine lesions;
• restaging (to detect residual, recurrent or progressive disease);
• assessing SSTR expression status, both visually as well as using semi-quantitative parameters (like SUV), since patients with SST receptor-positive tumours are more likely to respond to octreotide therapy;
• selecting patients with well differentiated and metastatic neuroendocrine tumours for target somatostatin receptor radionuclide therapy (with ¹⁷⁷Lu or ⁹⁰Y-labelled DOTA- somatostatin analogues);
• obtaining prognostic data (patient with lesions showing higher Gallium-68 somatostatin analogues uptake generally present a better prognosis).
• Limited data is available on the potential use of Gallium-68 somatostatin analogues PET/CT for non-neuroendocrine SSTR expressing disorders, particularly if treatment with radiolabelled therapeutic SST analogues is under consideration.

10.6.4 Contra-indications

• 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).

10.6.5 Clinical performances

Literature data indicate that Gallium-68 somatostatin analogues PET/CT imaging have good diagnostic performance for the evaluation of NEN, better than somatostatin receptor scintigraphy (which has been the previous standard method) and conventional imaging procedures. A recent meta-analysis including a total of 2,105 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) [265]. Image reading has a good interobserver agreement [266]. Overall, PET/CT is safe and influences management in a large proportion of patients [267].

10.6.6 Activities to administer

The suggested activities to administer are:

• [⁶⁸Ga]Ga -DOTA-NOC, TOC & TATE: 100-200 MBq
• No recommendations are given for paediatric nuclear medicine.

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.

10.6.7 Dosimetry

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 [268,269].

The range in effective dose for [⁶⁸Ga]Ga -DOTA-TATE is: 2.3-4.6 mSv per procedure.

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."

10.6.8 Interpretation criteria/major pitfalls

Uptake outside the physiologic biodistribution sites is considered pathologic.

Physiological biodistribution: pituitary gland, spleen (including accessory spleens), liver, adrenal glands, head of the pancreas, thyroid (very mild up-take) and the urinary tract (kidneys and urinary bladder).

False positive findings: activated lymphocytes (inflammation/infection/lymphoma), accessory spleen, pancreatic uncinated process.

False negative findings: small lesions dimension (<5 mm) and tumours with low or variable expression of SSTR (medullary thyroid carcinoma, neuroblastoma, insulinoma, pheochromocytoma, high grade NEN).

10.6.9 Patient preparation

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.

10.6.10 Methods

The detailed recommendations regarding Gallium-68 somatostatin analogues PET/CT imaging are available in the EANM Guidelines.