Galyum-68 DOTA-TATE PET/CT

Indıcation

In case of patients with an neuroendocrine tumor, Ga-68 DOTA-TATE PET/CT imaging is indicated for

1) locating the primary tumor,

2) initial staging,

3) restaging,

4) determining the somatostatin receptor status of tumors,

5) planning Lu-177 DOTA-TATE therapy and

6) evaluating treatment response.

What is Gallium-68 DOTA-TATE PET/CT? How Does it Show Tumor Foci?

The term ‘theranostic’ means a new field of medicine which involves integration of imaging and treatment into a single system and allows for concurrent specific treatment and follow-up.

In case of neuroendocrine tumors, tumor tissues can be visualized with Ga-68 DOTA-TATE with high sensitivity and specificity, while Lu-177-DOTA-TATE provides for specific and targeted therapies for tumor tissues. This is a rather new and successful method of theranostic procedures.

Neuroendocrine Tumors (NETs)

NETs refer to a relatively rare and heterogeneous group of tumors and the incidence is about 7.0/100.000. The most common type is a gastroenteropancreatic (GEP) NET, which accounts for more than 90% of patients with NETs. Depending on the origin, they are classified as gastric, pancreatic, small intestine, colorectal and unspecified primary. In addition to GEP-NETs, there are several subtypes of NETs including pheochromocytoma, paraganglioma, medullary thyroid carcinoma, Markel cell carcinoma and bronchial carcinoids.

Somatostatin Receptors (SSTRs)

Somatostatin is a native hormone and it works by binding to SSTRs which is strongly expressed in majority of NETs. There are 5 dominant subtypes of SSTRs and SSTR; Type 2 is the most commonly expressed one in NETs. Somatostatin analogues, like octreotide and lanreotide, exert their therapeutic effects by activating SSTRs, thus slowing down tumor growth and inhibiting tumor-induced hormone secretion. Presence of SSTRs enables somatostatin analogues to be used for “imaging” by labeling them with radioactive elements, like Gallium-68, and for treatment by labeling them with radioactive elements, such as Lu-177.

Which agents are used in SSTRs PET/CT?

DOTA-TATE, DOTA-TOC and DOTA-NOC peptides labeled with Gallium-68 have been developed to be used in SSTRs-targeted PET/CT imaging. There is no significant difference between these peptides when used for imaging. All these agents bind to SSTR type 2 and exhibit different affinity profiles for other SSTRs subtypes.

What are the advantages of Gallium-68 DOTA-TATE PET/CT?

Many scientific studies demonstrate that Ga-68 DOTA-TATE PET/CT imaging is superior to conventional imaging techniques (e.g. SSTR scintigraphy, CT, MRI). Ga-68 DOTA-TATE PET/CT not only locates the primary tumor, but it also shows other lesions that cannot be visualized in conventional imaging studies. This translates into alteration in management of approximately one third of the patients due to better staging.

Although Ga-68 DOTA-TATE PET/CT is the most appropriate imaging technique for GEP-NETs according to evidences, it is a fact that this imaging technique is invaluable for many SSTRs-positive diseases. A clinical study demonstrated that using Ga-68 DOTA-TATE PET/CT imaging alter the clinical approach in case of 70% of the patients.

Tumors with High SSTRs Expression

GEP NETs, functioning/nonfunctioning (e.g. carcinoid, gastrinoma, insulinoma, glucagonoma, VIPoma etc.)
Sympatho-adrenal system tumors (pheochromocytoma, paraganglioma, neuroblastoma, ganglioneuroma)
Medullary thyroid cancer
Pituitary adenoma
Medulloblastoma
Merkel Cell Carcinoma
Small cell lung cancer (particularly primary tumors)
Meningioma

Tumors with Low SSTRs Expression

Breast cancer
Melanoma
Lymphomas
Prostate cancer
Non-small cell lung cancer
Sarcomas
Renal Cell Carcinoma
Differentiated thyroid cancer
Astrocytoma
Ependymoma

Role of Gallium-68 DOTA-TATE PET/CT in Pediatric Patients

Ga-68 DOTA-TATE PET/CT is a functional imaging method and is recommended for pediatric NETs. This technique is also recommended to investigate neuroblastoma, paraganglioma and pheochromocytoma particularly in case of negative MIBG imaging. As meningiomas also express SSTR in children and adolescents with neurofibromatosis type 2, they can be detected on Ga-68 DOTA-TATE PET/CT scan.

Is Gallium-68 DOTA-TATE PET/CT Safe?

For typical dose of 185 MBq (5 mCi) activity, the estimated total amount of body radiation dose is 4.8 mSv for Ga-68 DOTA-TATE, and this dose is comparable to the radiation exposure caused by a conventional modality, such as computed tomography. The value is 7.0 mSv for oncologic PET/CT imaging that uses F-18-FDG at dose of 370 MBq (10 mCi).

No side effect of 68Ga-DOTA-peptides has been reported.

The amount of peptide (Ga-68 DOTA-TATE) administered into the body is less than 50 μg and no clinically significant pharmacological effect is observed with such an amount.

Ga-68 DOTA-TATE PET/CT is a safe imaging method also for infants, children and young adults.

In case of lactation, breastfeeding should be stopped and breast milk should be pumped out and disposed of during 12 hours after the injection of Ga-68 DOTA-TATE to minimize baby’s exposure to radiation.

Who Are the Candidates for Gallium-68 DOTA-TATE PET/CT?

Classical Indication

Locating the primary tumor: Detecting the primary focus in patients with documented metastatic disease.
Re-staging: Detecting residual disease, relapse or progression in patients with documented NETs.
Determining SSTRs status of tumor: Use of semi-quantitative parameters such as visual or maximum SUV (The probability of response to octreotide therapy is higher in patients with SSTR-positive tumor)
Planning Lu-177 DOTA-TATE therapy: Selecting the patients with metastatic disease.
Evaluation of treatment response: It should be known that changes in receptor status do not always respond to the treatment and the dedifferentiation associated with receptor loss should be taken into consideration.
Initial staging: Investigating metastatic foci after histopathological diagnosis is made.

Other Clinical Scenarios for use of Gallium-68 DOTA-TATE PET/CT

Restaging before elective surgery: e.g. surgical cytoreduction
Evaluating masses leading to NETs suspect that are not suitable for endoscopic-percutaneous biopsy. e.g. ileal lesion, hypervascular pancreatic mass, mesenteric mass
Follow-up of NETs identified particularly on Ga-68 DOTA-TATE PET/CT
Evaluating patients with biochemistry findings and symptoms of NETs, but with negative conventional imaging studies or without histopathological diagnosis of NETs.

Considerations for Tumor Grade and Imaging Method

NETs vary by aggressiveness of tumor and they are categorized through histological evaluation. Classification depends on location or origin of the tumor. Gastroenteropancreatic NETs are typically classified according to Ki-67 proliferation index or number of mitoses. Well-differentiated NETs (G1 and G2) have a relatively slow progress and long-term survival may be achieved even if there is a metastatic disease. Typically, high-grade (G3) poorly differentiated neuroendocrine carcinomas are more aggressive and almost always metastatic when diagnosed. In high-grade NETs, SSTR positivity is variable, and F-18-FDG PET/CT usually works better in such patients. On the other hand, Ga-68 DOTA-TATE PET/CT results may be positive for “well differentiated G3 tumor” and Ga-68 DOTA-TATE PET/CT may be helpful to detect patients who are candidates for PRRT.

GEP NETs Classification

Differentiation	Grade	Ki-67:	Proliferation rate	SSTR Positivity
Well differentiated.	Low-G1	<%3	<2 mitoses/10hpf	+++
	Intermediate-G2	%3-20	2-20 mitoses/10hpf	++
Poorly differentiated	High-G3	>%20	>20 mitoses/10hpf	variable

Preparation before Gallium-68 DOTA-TATE PET/CT

While an appointment is scheduled, relevant personnel provide detailed information about the procedure and its preparation.

Some practitioners recommend to discontinue “cold” octreotide therapy (if possible and if not contraindicated) to avoid possible SSTRs blockage. The interval from cessation of treatment to Ga-68 DOTA-TATE PET/CT depends on the type of medications. One day is sufficient for molecules with short half life, while it is recommended to wait for 3-4 weeks for long-acting analogues. On the other hand, many centers do not stop octreotide therapy before PET/CT scan. In this case, the best option is to perform PET/CT scanning immediately before the administration of long-acting octreotide.

Fasting is not required before the injection.

All necessary details are reviewed by Nuclear Medicine Specialist for optimal review of images:

History of suspicious or documented primary tumor.

Presence/absence of functional symptoms

Laboratory test results (hormones or tumor markers)

Results of other imaging studies (CT, MRI, Octreotide Scan, Ultrasound, X-ray)

Date of thelast biopsy, surgery, chemotherapy, radiotherapy or radionuclide therapy

Date of last SST analogue (octreotide) therapy

How is Gallium-68 DOTA-TATE PET/CT scanned?

Dose of 68Ga-DOTA peptide (DOTA-TOC, DOTA-NOC, DOTA-TATE)

The recommended activity ranges from 100 to 200 MBq.

Minimum activity recommended for high image quality is 100 MBq.

Activity is reduced in case of pediatric patients. The dose recommended for pediatric patients: 2 MBq (0.054 mCi)/kg body weight and maximum 200 MBq (5.4 mCi).

The dose of Ga-68 DOTA peptides should be less than 50 μg. No clinically significant pharmacological effect is observed with such amount.

Imaging

Total body images (from the head to mid thigh) are obtained using a PET/CT scanner, preferably 60 minutes after the injection.

Physiological biodistribution of 68Ga-DOTA peptides

Ga-68 DOTA peptides are cleared rapidly from the blood and no radioactive metabolite is observed in serum or urine 4 hours after the injection. It is almost entirely excreted by kidneys.

Organs with SSTRs expression;

Liver

Spleen

Pituitary gland

Thyroid

Kidneys

Adrenal glands

Salivary glands

Gastric wall

Intestines

Pancreas; SST receptor 2 is abundantly present in pancreatic islet cells (most frequently at pancreatic head) and may mimic focal tumor tissue.

The prostate gland and the glandular tissue of breasts may show diffuse low-grade Ga-68 DOTA peptides uptake.

Evaluation of images

Normal physiological distribution and abnormal uptakes are visually evaluated by a Nuclear Medicine Specialist. For tissues without physiological Ga-68 DOTA peptides uptake, accumulation of peptides or accumulations higher than the background activity can be considered pathological. Ga-68 DOTA peptides uptake higher than the uptake by the liver is a positive finding that indicates SSTRs expression, suggestive of a malignancy. Moderate, non-focal segmented intestinal uptakes are not pathologic. Variable physiological Ga-68 DOTA peptides uptake is observed in the pancreas, and focal uptakes may be observed, particularly at the pancreatic head.

Possible mistakes

Diffuse physiological Ga-68 DOTA-TATE uptake is observed in the spleen (and accessory spleen, if any), kidneys and pituitary gland. It may be mild in the thyroid and salivary glands.

Variable uptake is frequently observed in the pancreas for “physiological presence of SST receptor 2”.

Octreotide therapy or endogenous SST production (by tumor) may affect detection of tumor (decrease or increase detectability of tumor).

Variable tumor differentiation and heterogeneous expression of SSTRs subtypes may affect Ga-68 DOTA-TATE affinity and, therefore, the diagnostic performance.

Positive results of Ga-68 DOTA-TATE PET/CT represent increased density of SSTRs rather than a malignant disease. Uptake is not specific for malignant tumors. In case of positive results, other possible conditions characterized by high SSTRs, such as meningioma and active lymphocytes in the area of inflammation, should be taken into consideration.

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