Gallium-68 DOTA-TATE PET/CT
What is Gallium-68 DOTA-TATE PET / CT, how does it reveal tumor focus?
Theranostic; It is a concept and a new field of medicine that expresses the integration of imaging and treatment into a single system, allowing simultaneous specific treatment and its follow-up.
In neuroendocrine tumors, while Ga-68 DOTA-TATE can visualize tumoral tissues with high sensitivity and specificity; Specific and targeted treatment of these tumoral tissues is performed with Lu-177 DOTA-TATE. This is a very successful and new method for theranostic applications.
Neuroendocrine tumors (NET)
NETs encompass a relatively rare heterogeneous group of tumors, and their incidence is approximately 7.0 per 100,000. The most common type are gastroenteropancreatic (GEP) NETs and comprise more than 90% of all NET patients. According to their place of origin; They are classified as gastric, pancreatic, small intestine, colorectal, and an unknown primary. In addition to GEP-NETs, there are many NET subtypes, including pheochromocytoma, paraganglioma, medullary thyroid cancer, Merkel cell cancer, and bronchial carcinoids.
Somatostatin receptors (SSTR)
Somatostatin is a natural hormone that acts by binding to SSTR, a receptor overexpressed on most NETs. There are 5 dominant subtypes of SSTR and SSTR type 2 is the most frequently expressed in NETs. Somatostatin analogs such as octreotide and lanreotide exert their therapeutic effects by activating SSTRs, slowing tumor growth, and inhibiting tumor-associated hormone secretion. The presence of SSTRs means “imaging” by somatostatin analogs labeled with radioactive elements such as Gallium-68 and “treatment” by somatostatin analogs labeled with radioactive elements such as Lu-177.
Which agents are used in SSTR PET / CT?
Gallium-68 labeled DOTA-TATE, DOTA-TOC and DOTA-NOC peptides targeting SSTR have been developed to use in PET / CT imaging. When these peptides are used for imaging, there is no significant difference between them. All of these agents bind to SSTR type 2, while showing different affinity profiles for other SSTR subtypes.
What are the advantages of gallium-68 DOTA-TATE PET / CT?
In many scientific studies; Ga-68 DOTA-TATE PET / CT imaging has been shown to be superior to conventional imaging (eg, In-111 SSTR scintigraphy, CT, MR). While Ga-68 DOTA-TATE PET / CT detects the primary tumor site, it also often shows additional lesions that cannot be detected by conventional imaging. This leads to a change in the management of about one third of patients, with better staging.
Although GEP-NETs are the most appropriate disease group for Ga-68 DOTA-TATE PET / CT, due to sufficient evidence support, it is a fact that this imaging method is also valuable in many SSTR positive diseases. In a clinical trial, it was shown that using Ga-68 DOTA-TATE PET / CT imaging resulted in a change in clinical approach in 70% of patients.
Tumors with high SSTR expression
· GEP NET, functional / non-functional (eg carcinoid, gastrinoma, insulinoma, glucagonoma, VIPoma etc.)
· Sympathoadrenal system tumors (pheochromocytoma, paraganglioma, neuroblastoma, ganglioneuroma)
· Medullary Thyroid Carcinoma
· Pituitary Adenoma
· Medulloblastoma
· Merkel Cell Carcinoma
· Small Cell Lung Cancer (mainly primary tumors)
· Meningioma
Tumors with low SSTR expression
- Breast cancer
- Melanoma
- Lymphomas
· Prostate carcinoma
· Non-small cell lung cancer
· Sarcomas
· Kidney cell carcinoma
· Differentiated thyroid carcinoma
· Astrocytoma
· Ependymoma
The role of gallium-68 DOTA-TATE PET / CT in the pediatric population
Ga-68 DOTA-TATE PET / CT is the recommended functional imaging modality for pediatric NETs. It is also recommended for evaluation of neuroblastoma, paraganglioma and pheochromocytoma, especially in cases where mIBG imaging is negative. Since meningiomas in children and adolescents with neurofibromatosis type 2 also express SSTR, Ga-68 can be detected on DOTA-TATE PET / CT.
Is Gallium-68 DOTA-TATE PET / CT safe?
The estimated total body radiation dose is 4.8 mSv for the typical injected dose of 185 MBq (5 mCi) activity of Ga-68 DOTA-TATE, which is similar to the dose exposed by a conventional examination such as computed tomography. In oncologic PET / CT imaging performed by injecting 370 MBq (10 mCi) F-FDG, this value is 7.0 mSv.
No side effects associated with the administration of 68Ga-DOTA-peptides have been reported.
The amount of peptide (Ga-68 DOTA-TATE) injected is less than 50 μg and no clinically significant pharmacological effect is seen at these amounts
Ga-68 DOTA-TATE PET / CT is also a safe imaging method in infants, children and young adults.
In breastfeeding patients, breastfeeding should be discontinued for 12 hours after Ga-68 DOTA-TATE injection and breast milk should be pumped out and disposed to minimize baby’s exposure to radiation.
Who is Gallium-68 DOTA-TATE PET / CT applied to?
Classical Indications
- In the localization of the primary tumor: Determination of the primary focus in patients with known metastatic disease.
- In the first staging: Investigation of metastatic foci after histopathological diagnosis.
- In restaging: Detection of residual, recurrent or progressive disease in patients with known NETs.
- In determining tumoral SSTR status: use of semi-quantitative parameters such as visual or maximum SUV (Patients with SSTR positive tumors are more likely to respond to octreotide therapy.)
- In planning Lu-177 DOTA-TATE treatment: Selection of patients with metastatic disease.
- In evaluating the response to treatment: It should be known that the change in receptor status does not always respond to treatment and dedifferentiation accompanied by loss of receptor should be taken into account.
Other clinical scenarios in the use of Gallium-68 DOTA-TATE PET / CT
- In restaging prior to planned surgery: eg. surgical cytoreduction
- In the evaluation of suspected NET masses not suitable for endoscopic or percutaneous biopsy: eg. ileal lesion, hypervascular pancreatic mass, mesenteric mass
- Mainly in the follow-up of NETs detected on Ga-68 DOTA-TATE PET / CT
- In the evaluation of patients with biochemical findings and NET symptoms, but with negative conventional imaging or without a histopathological diagnosis of NETs
Tumor grade and considerations in imaging method
NETs are diversified according to their tumor aggressiveness and categorized by histological evaluation. The classification depends on the tumor site or origin. Gastroenteropancreatic NETs are typically classified based on Ki-67 proliferation index or mitotic count. Well-differentiated (G1 and G2) NETs have a relatively slow prognosis and years can be mentioned about prognosis even in the presence of metastatic disease. High-grade (G3) poorly differentiated neuroendocrine carcinomas are typically much more aggressive and almost always metastatic at the time of diagnosis. SSTR positivity is variable in high-grade NETs and often 18F-FDG PET / CT performs better in these patients. Ga-68 DOTA-TATE PET / CT may be positive in the “well-differentiated G3 tumor” subtypes, and Ga-68 DOTA-TATE PET / CT imaging can be helpful in finding patients who are candidates for PRRT.
GEP NET classification
| Differantiation | Grade | Ki-67 | Proliferation Rate | SSTR Positivity |
| Well differantiated | Low-G1 | <%3 | <2 mitosis/10hpf | +++ |
| Medium-G2 | %3-20 | 2-20 mitosis/10hpf | ++ | |
| Poor differantiated | High-G3 | >%20 | >20 mitosis/10hpf | Variable |
Preparation before galyum-68 DOTA-TATE PET/BT
During the appointment, a detailed explanation about the procedure and patient preparation is made by the relevant personnel.
To avoid possible SST receptor blockage, patients are advised by some practitioners to discontinue “cold” octreotide therapy (if possible and not contraindicated). The time interval between discontinuation of treatment and Ga-68 DOTA-TATE PET / CT depends on the type of drugs used. While 1 day is sufficient for short-lived molecules, 3-4 weeks are recommended for long-acting analogues. However, octreotide therapy is not discontinued before PET / CT scan in many centers. In this case, the best option would be to perform the PET / CT study just before the planned monthly long-acting octreotide dose.
Fasting is not required before injection.
All information useful for optimal interpretation of images is reviewed by the Nuclear Medicine Physician:
- History of suspected or known primary tumor
- Presence / absence of functional symptoms
- Laboratory test results (hormone or tumor marker levels)
- Results of other imaging methods (CT, MR, ultrasonography, plain radiography)
· Date of last biopsy, surgery, chemotherapy, radiotherapy or radionuclide therapy
· History of last SST analogues (octreotide) therapy
How is Gallium-68 DOTA-TATE PET / CT Performed ?
68Ga-DOTA peptide dose administered (DOTA-TOC, DOTA-NOC, DOTA-TATE)
Recommended activity ranges from 100 to 200 MBq.
The minimum recommended activity getting a quality image is 100 MBq.
Activity is reduced in pediatric patients. Recommended dosage in pediatric patients; It is 2 MBq (0.054 mCi) / kg body weight and a maximum of 200 MBq (5.4 mCi).
The amount of 68Ga DOTA peptide injected should be less than 50 μg. Clinically significant pharmacological effects are not expected at these amounts.
Imaging
Using PET / CT, images in the form of a whole body scan, preferably including the middle of the head and leg, are obtained at 60 minutes after injection.
Physiological biodistribution of 68Ga-DOTA peptides
68Ga-DOTA peptides are rapidly cleared from the blood and no radioactive metabolites are detected in serum or urine 4 hours after injection. Almost all excretion occurs through the kidneys. [18].
- Organs showing SSTR expression;
Liver
Spleen
Pituitary Gland
Thyroid
Kidneys
Adrenal Glands
Salivary Glands
Stomach Wall
Bowel
Pancreas; SST receptor 2 is particularly concentrated in pancreatic islet cells (most commonly found in the head of the pancreas) and can mimic focal tumor tissue.
The prostate gland and mammary glandular tissue may show diffuse low-grade 68Ga-DOTA peptide uptake.
Evaluation of images
Normal biological distribution and abnormal involvements are evaluated visually by the Nuclear Medicine physician. In structures that do not physiologically retain 68Ga-DOTA peptides, the accumulation of these peptides or higher than background activity can be considered pathological. The higher 68Ga-DOTA peptide uptake compared to liver involvement is a positive finding indicating increased SSTR expression and indicates malignancy. Moderate, non-focal segmental intestinal involvement is not pathological. Variable physiological 68Ga-DOTA peptide uptake is observed in the pancreas, and focal involvement can be observed, most frequently in the head of the pancreas.
Possible sources of error
Intense physiological Ga-68 DOTA-TATE uptake is seen in the spleen (and accessory spleen if present), kidneys, and pituitary gland. Thyroid and salivary glands are slightly visible.
Variable involvement is often found in the pancreas due to the “physiological presence of SST receptor 2”.
Octreotide treatment or endogenous SST production (by the tumor) may affect tumor detection (decrease or increase tumor detectability).
Variable tumor differentiation and heterogeneous expression of SST receptor subtypes can affect the affinity of Ga-68 DOTA-TATE and thus diagnostic performance.
Positive findings for Ga-68 DOTA-TATE PET / CT reflect the increased density of SST receptors rather than malignant disease. Uptake is not specific for malignant tumors. In positive results, other possible conditions such as meningioma, activated lymphocytes in inflammation which are characterized by the presence of high SSTR sites should also be evaluated.