non-pet tumor imaging p7_somatostatin receptor imaging

Jiraporn Sriprapaporn, M.D.

Nuclear Medicine

Siriraj Hospital

Mahidol University

Non-PET Oncologic Imaging_Jiraporn

Radiopharmaceuticals for Non-PET Oncologic Applications

Nonspecific

• Ga-67 citrate:

– Lymphoma

• Tl-201 chloride:

– Bone sarcomas

– Brain tumors

– Thyroid cancer

• Tc-99m sestamibi:

– Breast cancer

– Parathyroid adenoma

– Thyroid cancer

• Tc-99m tetrofosmin: Similar to sestamibi

Tumor-Type Specific

• I-131: Diff thyroid cancer (PTC, FTC)

• I-131 MIBG: Neural crest tumors (adrenal medullary imaging)

• Radiolabeled peptides, Somatostatin receptors:

– In-111 pentetreotide (OctreoScan): Neuroendocrine tumors

– Tc-99m HYNIC-TOC: NETs

– Tc-99m depreotide*: Lung cancer

• Radiolabeled monoclonal antibodies:

– Tc-99m arcitumomab (CEA-Scan)*: Colorectal cancer

– In-111 capromab pendetide (ProstaScint): Prostate cancer

REF : modified from The Requisites


Somatostatin Receptor Scintigraphy (SRS) for Neuroendocrine Tumors (NETs)

Radiopharmaceuticals

• In-111 pentetreotide (OctreoScan)

• Tc-99m HYNIC-TOC


Peptide Receptor Scintigraphy

• Peptides are biologically occurring short chains

of amino acid linked by peptide (amide) bonds.

– Ex. Dipeptides – 2 aa. = shortest peptides

– Somatostatin receptor scintigraphy

– Vasoactive intestinal peptide receptor scintigraphy.

– Others

• Somatostatin is a peptide hormone, 2 active

forms:- 14-aa. & 28-aa.


2011

2010


Somatostatin

• Endogeneous somatostatin, known as growth hormone-inhibiting hormone (GHIH) or somatotrophin release inhibiting factor (SRIF), 2 active forms

– 28-amino acid peptide

– 14-amino-acid peptide, 2-3-minute half-life.

– SS-28 is roughly ten-fold more potent in inhibition of growth hormone secretion, but less potent that SS-14 in inhibiting glucagon release.

• It is produced in the hypothalamus, pituitary gland, brainstem, GI tract, and pancreas.

• In the CNS, it acts as a neurotransmitter.

• Outside of the brain, it functions as a hormone inhibiting release of growth hormone, insulin, glucagon, gastrin, serotonin, and calcitonin.

• It appears to play a role in angiogenesis inhibition, is involved in the immune function of white blood cells, and has an antiproliferative effect on tumors.

The Requisites


Somatostatin Receptors (SSTR)

• At least 5 different subtypes of human somatostatin receptors (SSTR) have been identified (SSTR1 to SSTR5).

• These receptors are expressed to varying degrees on different tumors.

• The commercially available radiopharmaceutical In-111 pentetreotide binds with high affinity to the SSTR2 and SSTR5 subtypes, to a lesser extent with SSTR3, and not at all with SSTR1 or SSTR4.

• Identifying the specific receptor subtypes on tumors is also important as future targeted therapeutic agents.


Somatostatin Receptor Scintigraphy (SRS)

• Endogeneous Somatostatin is a 14-amino-acid peptide with 2-3 minute biol. half-life.

• Octreotide is an 8-amino-acid peptide that maintains the ability to bind to native hormone receptors but is resistant to enzymatic degradation with a 1.5-2 hour half-life.

– Nonradiolabeled octreotide (Sandostatin) has been approved by the U.S. Food and Drug Administration (FDA) as a therapeutic agent, suppressing growth in acromegaly and controlling symptoms in carcinoid syndrome.

– Radiolabeled octreotide used for

somatostatin receptor scintigraphy (SRS)


Radiopharmaceuticals for SRS

• I-123 Octreotide : [3-123I-Tyr3] octreotide (1980s)

• In-111-pentetreotide [In-111-DTPA-D-Phe] octreotide] Octreoscan®, Mallinckrodt Inc. [In-111 Octreotide]

• Tc-99m HYNIC-TOC: Tc-99m hydrazinonicotinyl-Tyr(3)-octreotide

• Tc-99m depreotide (Tc-99m-NeoTect; Diatide, Inc.) is also registered in Europe

Ambrosin V, JNM 2011


Radiopeptide PET Tracers

• 68Ga-labeled somatostatin analogs used in the clinic are based on the 3 octapeptides [Tyr3]octreotide (TOC), [Tyr3,Thr8]octreotide (TATE), and [1-Nal3]octreotide (NOC) conjugated to DOTA.

Ambrosin V, JNM 2011


Doina Piciu Nuclear Endocrinology, 2012

• The octreotide is a somatostatin analogue with the structure:

• D-Phe 1 -Cys 2 -Phe 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 -Thr 8 (ol)

• Researchers found that if Phe 3 is substituted with Tyr 3 it is possible to labeled with radioiodine isotopes, both for diagnostic and for therapy.

• D-Phe 1 -Cys 2 -Tyr 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 -Thr 8 (ol)

• Octreotide was derivatized with diethylenetriaminepentaacetic acid (DTPA) on the amine terminus. Attaching this chelate to the peptide allowed radiolabelling of the molecule with In-111. In-111 pentetreotide

• Following that step, with the aim to find the best agent for PRRT, the chelating agent, DTPA, (coupled to octreotide) was substituted with DOTA (tetra-aza-cyclo-dodecane-tetraacetic acid), which enabled the radiolabelling of this conjugate with Y-90, Lu-177 or other radionuclides.

• DOTATOC : DOTA-Phe 1 -Tyr 3 -Octreotide

• DOTANOC: DOTA-Nal 3 -Octreotide (DOTA Naphythyl-alanine conjugate with octreotide)

• Octreotate is another peptide analogue of somatostatin, which differs from octreotide where

• the C-terminal amino acid residue is threonine (instead of threoninol in octreotide)

• DOTATATE: DOTA-Thy 3 -Thre 8 –Octreotide (Octreotate)


Somatostatin Analogues

Storch D, JNM 2005

(Octreoscan)


Somatostatin Receptor Radiopharmaceuticals

Somatostatin Receptor Radiopharmaceuticals

Octreotide

I-123 Octreotide

In-111 Pentetreotide

(DTPA)

Tc-99m HYNIC-TOC

Ga-68 DOTA-TOC

Ga-68 DOTA-NOC

Octreotate Ga-68 DOTA-TATE


Radiopharmaceuticals

• 111In-pentetreotide (OctreoScan) is an agent used primarily for scintigraphic localization of primary and metastatic neuroendocrine tumors bearing somatostatin receptor (SSTR).

• 111In-pentetreotide is [111In-DTPA-D-Phe] octreotide, a somatostatin analog that binds to somatostatin receptors on cell surfaces.

• This octapeptide binds to somatostatin receptor–rich normal tissues and concentrates in NETs and some non-NETs containing somatostatin receptors (predominantly SSTR subtypes 2 and 5).

• Patients with positive 111In-pentetreotide images are also candidates for octreotide therapy because the documentation of SSTR provides a higher likelihood of controlling hormonal hypersecretion.

• Radionuclide therapy for octreotide-avid carcinoid tumors has been tried with various degrees of success using iodine-131 or yttrium-90 labeled octreotide.


Indium-111 Pentetreotide (or In-111 Octreotide Scan)

Pharmacokinetics and Dosimetry

• In-111-DTPA-pentetreotide (OctreoScan®; Mallinckrodt, Hazelwood, MO) involves complexing octreotide with diethylenetriaminepentaacetic acid (DTPA) to bind In-111.

• In-111 pentetreotide is rapidly cleared by the kidneys, with 50% of the dose excreted by 6 hours and 85% by 24 hours after injection.

• A low level (2%) of hepatobiliary excretion also occurs.

• At 4 hours after injection, 10% of the dose remains in circulation; at 20 hours, less than 1% is in circulation.

• Whereas rapid clearance enhances the target-to-background ratio, bowel activity increases over time and can cause problems detecting abdominal lesions ( Fig. 12-3 ).

• Organ receiving highest dose = spleen (Table 12-2 , The Requisites)


Indium-111 Pentetreotide Scan

Imaging protocol

• WB images are routinely acquired at 24 h. (4-h and 48-h

postinjection imaging is optional.)

• SPECT/CT at 24 h.

• large-field-of-view, gamma camera fitted with a medium-energy

collimator.

• 20% energy windows are centered over both photopeaks of 111In

(173 and 247 keV),


111 In-pentetreotide Scan: Normal Distribution

• Blood pool,

• Pituitary gland

• Thyroid gland

• Kidneys (+renal parenchyma) and bladder,

• Liver, gallbladder, spleen*

• bowel on delayed images.

• The kidneys and spleen retain the most activity.


Clinical Indications of In-111 pentetreotide

Tumors with High Expression of SSR

1. Adrenal medullary tumors

– pheochromocytoma, neuroblastoma, ganglioneuroma, paraganglioma

2. Gastroenteropancreatic (GEP) NETs (formerly termed carcinoid, gastrinoma, glucagonoma, vasoactive intestinal polypeptide-secreting tumor, pancreatic polypeptide-secreting tumor, etc., or nonfunctioning GEP tumors), more recently classified by the WHO as low grade, intermediate grade and high grade (G1, G2, and G3)

3. Merkel cell tumor of the skin

4. Pituitary adenoma

5. Small cell lung carcinoma


Multiple Endocrine Neoplasia (MEN) Syndromes

Lesion MEN-I MEN-IIA MEN-IIB

Pituitary adenoma +

Pancreatic islet cell tumor +

Parathyroid adenoma + +

Pheochromocytoma + +

Medullary thyroid cancer + +

Ganglioneuroma +

The Requisites


Indium-111 Pentetreotide Sensitivity in Various Applications

HIGH Carcinoid Islet cell tumors -Gastrinoma, glucaganoma, VIPoma Adrenal medullary tumors -Pheochromocytoma, Neuroblastoma, Paragangliomas Small cell lung cancer

86%-95% 75%-100% >85% 80%-100%

MODERATE Medullary thyroid carcinoma Insulinoma Medulloblastoma Meningioma

50%-75% 25%-70% 61%-93% 50% and 100% reported

LOW Pituitary adenoma Astrocytoma grade IV (higher in grades I and II) Breast cancer Melanoma Renal cell carcinoma

The Requisites


Clinical Applications of SRS on NETs

• Most (> 85%) of NETs have SSTR 2 & 5.

• The sensitivity of SRS has been estimated to be in the range of 80–90% in patients with asymptomatic GI NETs and > 90% in patients with symptoms of carcinoid syndrome

• SRS can also detect islet-cell tumors with the sensitivity of approximately 50% for insulinomas and 80–90% for other tumors. Failure to visualize some insulinomas may be related to higher affinity binding for somatostatin receptor type 3 than for types 2 or 5.

• Pancreatic adenocarcinomas typically are not detected on SRS.

Text: Neuroendocrine Tumors, 2011


False-positive Results

1. Autoimmune diseases (e.g., rheumatoid arthritis, Graves’ disease, Graves’ophthalmopathy)

2. Bacterial pneumonia

3. CVA

4. Fibrous dysplasia

5. Granulomatous diseases (e.g., TB, sarcoidosis)

6. Post radiation inflammation


False-negative Results

• Small size of tumors

• Tumors in adjacent area with physiologic

activity

• Amount & type of SSTR present


Pulmonary Carcinoids

• A, 4-hour and B, 24-hour anterior 111In pentetreotide images of the abdomen and chest show normal activity in the liver, kidneys, and bowel; however, an abnormal focus of activity is seen in the right lower chest (arrow).

• C, An abnormal enhancing lesion is seen on the CT scan.

• D, SPECT/CT fusion image clearly shows accumulation of 111In pentetreotide by this carcinoid.

Essentials NM


In-111 pentetreotide SPECT/CT images

• (A) localize a small focus of activity to a peripancreatic retroperitoneal lymph node, difficult to see on planar images and

• (B) show marked uptake in a precarinal nodal metastasis, which would be falsely called normal by CT size criteria.

The Requisites

99mTc-EDDA/HYNIC-TOC Imaging


99mTc-HYNIC-[Tyr3]-octreotide for imaging somatostatin-receptor-positive tumors: preclinical evaluation and

comparison with 111In-octreotide. Decristoforo C, et al. JNM 2000, PMID: 10855644

• 99mTc-hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC)

• HYNIC-TOC was radiolabeled at high specific activities using tricine, ethylenediaminediacetic acid (EDDA), and tricine-nicotinic acid as coligand systems.


99mTc-EDDA/HYNIC-TOC Imaging

• Scan time: 15 min to 20 hrs (1, 4 hrs)

• Normal distribution: liver, GB, spleen, kidneys, BL, bowel, thyroid

• Excretion via the kidneys and lesser extent via the GI tract

• 99mTc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111In derivatives, especially in relation to heart and muscle. [Decristoforo C, et al. EJNM 00]

Shas S, 2012 IJNM


Tc-99m HYNIC-TOC & Pancreatic NET with distant metastases

• (A) Uptake in the primary (arrow) and the metastatic lesions which are localized on the transaxial SPECT/CT images to correlate with the lesion in the skull (B), a enlarged prevascular node (C) and a tiny pleural based pulmonary nodule (D) which is identified on the correlative CT image (triangulated in E).

•

Shas S, 2012 IJNM

• Another pulmonary

nodule is seen as a

focus of uptake in the left

hemithorax on the whole

body planar image (A)


NET at duodenum with liver metastasis, presenting with diarrhea

Shas S, 2012 IJNM

99mTc-EDDA/HYNIC-TOC Imaging of

Anaplastic Thyroid CA

• Anaplastic thyroid carcinoma with cervical and lung metastases) at 15 min to 20 h post injection of 300 MBq of 99mTc-EDDA/HYNIC-TOC.

Decristoforo C, et al. EJNMM 2000

Carcinoids with high uptake in tumours in the hepatic and intestinal areas.

• Semi-quantitative analysis revealed similar tumour/organ ratios in liver and spleen for all tracers, but considerably higher ratios for 99mTc-EDDA/HYNIC-TOC for heart and muscle.

Decristoforo C, et al. EJNMM 2000

99mTc-tricine-HYNIC-TOC: Metastatic MTC

• 4-hr planar image of the posterior thorax.

• A lesion located in the posterior basal lobe of the left lung is visible. Histology: metastasis of a medullary thyroid carcinoma (7 mm)

Bangard M EJNM00 Decristoforo C, et al. EJNMM 2000

Cardiac Pheochromocytoma

FIGURE 1. A woman presented with dizziness,

palpitation, and perspiration.

Chen L, et al. CNM 07

http://jnm.snmjournals.org/content/vol50/issue3/images/large/397fig1.jpeg

non-pet tumor imaging p7_somatostatin receptor imaging

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