Download 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
Somatostatin Receptor Scintigraphy
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).
Basis of the clinical utility of radiolabelled specific ligands
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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)
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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)
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
SOMATOSTATIN
Peptide regulatory
CNS and peripheral tissues
Hypothalamus
Action:
Neurotransmitter
Other effects:
Antiproliferative
in tumors
Specific regulation
of immune responses
Hormonal effects:
Inhibitory peptide
GH
Insuline
Glucagon
Gastrin
Serotonin
Calcitonin
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Mediated by membrane receptors
SOMATOSTATIN EFFECTS
Cloned : sstr1 – sstr5
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RECYCLED
(resensitized)
INTERNALIZATION
Lysosome
Endosome
(dephosphorylation)
In-111 DTPA D-Phe OC
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Normal human tissues
SOMATOSTATIN RECEPTOR EXPRESSION
High incidence and density in human neoplasias
Pituitary adenomas
Pancreatic islet-cell tumors
Gastroenteral NE tumors (carcinoids)
Paragangliomas
Pheochromocytomas
SCLC
Medullary thyroid cancer
Non-endocrine
Non-neural cell tumors
Lymphoma
Breast cancer
Renal-cell cancer
Hepatocellular cancer
Prostate cancer
Sarcoma
Gastric carcinoma
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Simultaneous expression of multiple subtypes of sstr
DOMINATING EXPRESSION OF sstr 2
Inhibitory, antiproliferative and apoptotic effects
Basis for the clinical application of SA
Non-functioning pituitary adenomas: sstr3
Human hypophysis ≠ sstr 4
Prostate: sstr 1
~100% gastrinomas express sstr
10%-50% insulinomas express sstr
¿Tumors with dominant sstr 4 expression?
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
The expression of somatostatin receptors
Is not specific
of tumor diseases
Sarcoidosis: active granulomas
Rheumatoid arthritis: synovial vessels
Intestinal inflammatory disease: vascular
Tumoral or peritumoral
Blood vessels
Immune cells
Contaminant normal cells
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Servicio de Medicina Nuclear – Instituto Nacional de Cancerología
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Servicio de Medicina Nuclear – Instituto Nacional de Cancerología
23-03-06
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9-10-08
Servicio de Medicina Nuclear – Instituto Nacional de Cancerología
H - Ala - Gly - Cys - Lys - Asn - Phe -
D Phe
Phe
- Cys -
Trp
s
s
s
s
Lys
OH - Cys - Ser - Thr - Phe -
Somatostatin -14
Half-life < 3 min
Tre
Thr – Cys (ol)
Octreotide
Half-life: 6 h
DTrp
In111
- DTPA -
D Phe
- Cys -
Phe
DTrp
s
s
Thr – Cys (ol)
Lys
Thr
['"Indium-diethylene triamine pentaacetic acid°-D-Phe1] octreotide
('"In-Pentetreotide) OctreoScan®; Mallinckrodt.
10 µg of peptide; 222 MBq (6 mCi); 5 MBq/kg (0,14 mCi/kg) of Indium-111
No adverse effects < 50 µg
Physical half-life: 2,83 days
GaTc99m
68
HYNIC -- -DOTA
D Phe
- Cys -
- DTPA -
D Phe
DTrp
s
s
Thr – Cys (ol)
In111
Tyr
DTrp
s
Lys
Thr – Cys (ol)
Thr
99mTc-HYNIC-TOC
Phe
s
Lys
68Ga-DOTA-Tyr3-OC
- Cys -
Affinity
Affinity
111In-DTPA-OC
9 : 1
3 : 1
DPhe
Affinity for sstr2 (DTPA o DOTA):
14- to 17-fold >octreotide
8- to10-fold >TOC
Thr
- Cis -
Tyr
DTrp
s
s
Thr - Cys -
Lys
Thr
Octreotate
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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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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
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Servicio de Medicina Nuclear – Instituto Nacional de Cancerología
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Physiologic vs pathologic
gastric uptake
Biodistribution in time
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Spect corporal total:
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Servicio de Medicina Nuclear – Instituto Nacional de Cancerología
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Servicio de Medicina Nuclear – Instituto Nacional de Cancerología
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MOLECULAR IMAGING
Sensitivity
SPATIAL RESOLUTION vs MOLECULAR RESOLUTION
CT/ MR
Structural
mmol
PET/ SPECT
Metabolism
mol
pmol
nmol
1 mm
5 mm
10 mm
Spatial Resolution
Molecular resolution in the range of 2 nm
Sensitivity: capacity to detect a molecular marker
Courtesy: Dr. Diana Páez
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs
INDICATIONS
•
•
•
•
Search for primary tumor
Assess extent of disease
Assess treatment response.
Select patients for radionuclide
treatment
•
•
•
•
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.
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs
INDICATIONS
•
•
•
•
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.
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
Clinical Impact
IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs
Cost-benefit relationship
Avoids unnecessary surgery
Detects previously
undetected metastases
SPECT/CT
Enhances image interpretation
Precise anatomical localization (32%)
Further changes in management (14%)
Changes in management: 17% - 28%
Identification of new lesions
Clear up imaging findings
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
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
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
CONCLUSIONS I
1. SRS: to assess NETs and to identify candidates for
metabolic therapies
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
5. TOC and TATE: more affinity, higher internalization rate than octreotide
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NEUROENDOCRINE TUMORS
Somatostatin Receptor Scintigraphy
CONCLUSIONS II
6. Same peptide for diagnosis and therapy
7. New standard: [68Ga-DOTAº,Tyr3] Octreotide or
[68Ga-DOTAº,Tyr3] Octreotate