NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy
Transcript of NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Dr. Augusto Llamas Olier
Nuclear Medicine Department
Instituto Nacional de Cancerología
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Neuroendocrine tumors
Heterogeneous group of neoplasias derived from NE cells of the diffuse
endocrine system.
Characterized by:
Having neurosecretory granules
Producing bioactive amines (serotonine, catecholamines, histamine) and
polypeptidic hormones (somatostatin, gastrin).
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Basis of the clinical utility of radiolabelled specific ligands
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DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs
• I-131/I-123 Metaiodobencylguanidine (MIBG)
Cellular structures for amine uptake and storage
Prefered indications: pheocromocytoma (specif. 80-100%) and
neuroblastoma (specif. 84%).
Sensitivity: 36% - 85%
• Somatostatin analogs (SA)
Overexpression of receptors for regulatory peptides (i.e.,
somatostatin).
Sensitivity: 78% - 100% (Indium-111 DTPA –Octreotide)
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs
Other radioligands
• [68Ga-DOTA]-D-Phe1-Tyr3-Octreotide (68Ga-DOTA TOC)
• [68Ga-DOTA]-Tyr3-Octreotate (68Ga-DOTA TATE)
• [90Y-DOTA]-D-Phe1-Tyr3-Octreotide (90Y-DOTA TOC)
• [177Lu-DOTA ]-Tyr3-Octreotate (177Lu-DOTA TATE)
• [18F]-L-dihydroxyphenylalanine (18F-L-DOPA)
• [11C]-5-hydroxytryptophan (11C-5-HTP)
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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SOMATOSTATIN
Peptide regulatory
CNS and peripheral tissues
Hypothalamus
Action:
Neurotransmitter
Hormonal effects:
Inhibitory peptide
GH
Insuline
Glucagon
Gastrin
Serotonin
Calcitonin
Other effects:
Antiproliferative
in tumors
Specific regulation
of immune responses
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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Mediated by membrane receptors
Cloned : sstr1 – sstr5
SOMATOSTATIN EFFECTS
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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INTERNALIZATION
Endosome
(dephosphorylation)
RECYCLED
(resensitized)
Lysosome
In-111 DTPA D-Phe OC
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SOMATOSTATIN RECEPTOR EXPRESSION
Normal human tissues
High incidence and density in human neoplasias
Non-endocrine
Non-neural cell tumors
Lymphoma
Breast cancer
Renal-cell cancer
Hepatocellular cancer
Prostate cancer
Sarcoma
Gastric carcinoma
Pituitary adenomas
Pancreatic islet-cell tumors
Gastroenteral NE tumors (carcinoids)
Paragangliomas
Pheochromocytomas
SCLC
Medullary thyroid cancer
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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DOMINATING EXPRESSION OF sstr 2
Simultaneous expression of multiple subtypes of sstr
Prostate: sstr 1
Non-functioning pituitary adenomas: sstr3
Inhibitory, antiproliferative and apoptotic effects
Basis for the clinical application of SA
Human hypophysis ≠ sstr 4
~100% gastrinomas express sstr
10%-50% insulinomas express sstr
¿Tumors with dominant sstr 4 expression?
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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The expression of somatostatin receptors
of tumor diseases
Sarcoidosis: active granulomas
Rheumatoid arthritis: synovial vessels
Intestinal inflammatory disease: vascular
Is not specific
Tumoral or peritumoral
Blood vessels
Immune cells
Contaminant normal cells
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Phe
Trp
Lys
Tre
Ala - Phe - Asn -
Thr - Ser -
H -
Phe -
Gly - Cys - Lys -
Cys - OH -
s
s DTrp
Somatostatin -14 Octreotide
Half-life < 3 min Half-life: 6 h
D Phe - Cys -
Cys - Thr –
(ol)
s
s
Phe
DTrp
Lys
Thr
D Phe - Cys -
Cys - Thr –
(ol)
s
s
- DTPA - In-
111
('"In-Pentetreotide) OctreoScan®; Mallinckrodt.
10 µg of peptide; 222 MBq (6 mCi); 5 MBq/kg (0,14 mCi/kg) of Indium-111
-diethylene triamine pentaacetic acid°-D-Phe1] octreotide ['"Indium
No adverse effects < 50 µg
Physical half-life: 2,83 days
Tyr
DTrp
Lys
Thr
D Phe - Cys -
Cys - Thr –
(ol)
s
s
- DOTA - Ga-
68
68Ga-DOTA-Tyr3-OC
Phe
DTrp
Lys
Thr
D Phe - Cys -
Cys - Thr –
(ol)
s
s
- DTPA - In-
111
111In-DTPA-OC
Tyr
Thr -
Lys
Thr
Cis -
Cys -
s
s
DPhe -
DTrp
Octreotate
99mTc-HYNIC-TOC
Tc-
99m - HYNIC -
Affinity 9 : 1
Affinity for sstr2 (DTPA o DOTA):
14- to 17-fold >octreotide
8- to10-fold >TOC
Affinity 3 : 1
Higher affinity, higher rate of internalization, higher tumor uptake
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99mTc- Hynic-Tyr3-Octreotide 111In-DTPAº-Phe1-Octreotide
Nuclear Medicine Department – Instituto Nacional de Cancerología
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Characteristics of a good scintigraphic scan
• Dose: 222 MBq (6 mCi, adults), 5 MBq/Kg (0.14 mCi/Kg, children)
• Spect should have enough counts per projection
• 6-fold contrast enhancement
• Separate overimposed structures
• Enhanced diagnostic sensitivity
• High-count static images are better than wholebody scanning
• Special projections and delayed imaging to solve doubts
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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Characteristics of a good scintigraphic scan
• Dose: 222 MBq (6 mCi, adults), 5 MBq/Kg (0.14 mCi/Kg, children)
• Spect should have enough counts per projection
• 6-fold contrast enhancement
• Separate overimposed structures
• Enhanced diagnostic sensitivity
• High-count static images are better than wholebody scanning
• Special projections and delayed imaging to solve doubts SPECT/ CT
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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SPATIAL RESOLUTION vs MOLECULAR RESOLUTION
CT/ MR Structural
Molecular resolution in the range of 2 nm
Sen
sitiv
ity
Spatial Resolution
mmol
mol
pmol
nmol
1 mm 5 mm 10 mm
PET/ SPECT Metabolism
Sensitivity: capacity to detect a molecular marker Courtesy: Dr. Diana Páez
MOLECULAR IMAGING
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• Post surgical follow-up
• Screen for recurrences when
tumor markers are elevated
• Differential diagnosis between
NETs are space-occupying lesions
• Radioguided surgery of small
tumors/ confirmation of complete
resection.
• Search for primary tumor
• Assess extent of disease
• Assess treatment response.
• Select patients for radionuclide
treatment
IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs
INDICATIONS
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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• Post surgical follow-up
• Screen for recurrences when
tumor markers are elevated
• Differential diagnosis between
NETs are space-occupying lesions
• Radioguided surgery of small
tumors/ confirmation of complete
resection.
IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs
INDICATIONS
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs
Clinical Impact
Changes in management: 17% - 28%
Identification of new lesions
Clear up imaging findings
Avoids unnecessary surgery
Detects previously
undetected metastases
Cost-benefit relationship
SPECT/CT
Enhances image interpretation
Precise anatomical localization (32%)
Further changes in management (14%)
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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COMING UP
Somatostatin analogs labelled with positron emitters
ADVANTAGES OVER GAMMA EMITTERS
• Better affinity for sstr2
• Bind to other sstr: useful for non sstr2-expressing tumors
• Better spatial and molecular resolution
(detectability: SPECT 1-2 cm / PET 0,5-1 cm)
• Combined anatomic and metabolic information: better sensitivity
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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COMING UP
Somatostatin analogs labelled with positron emitters
[68Ga-DOTAº,Tyr3]Octreotide o [68Ga-DOTAº,Tyr3]Octreotate
• Multiple analogs in use with little infoormation exchange from center to
center.
• Will become the new standard in sstr-imaging
o High affinity for sstr2
o 68Ga: produced in generators / easy labelling on a daily basis
o90Y- and 177Lu -labelled counterparts are used for therapy
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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1. SRS: to assess NETs and to identify candidates for
metabolic therapies
CONCLUSIONS I
5. TOC and TATE: more affinity, higher internalization rate than octreotide
2. Tumor uptake: depends on affinity for sstr2 and rate of internalization
3. Small changes in peptide structure, chelating agents, radiometal
will enhace affinity and internalization rate.
4. [111Indio-DTPAº, Phe1] octreotide: current standard but not perfect
NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy