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Somatostatin Receptor Scintigraphy Dr Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Dr. Augusto Llamas Olier Nuclear Medicine Department Instituto Nacional de Cancerología Logo 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 Logo 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) Logo 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) Logo Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy SOMATOSTATIN Peptide regulatory CNS and peripheral tissues Hormonal effects: Other effects: Inhibitory peptide Hypothalamus Antiproliferative GH Action: in tumors Insuline Neurotransmitter Glucagon Specific regulation Gastrin of immune responses Serotonin Calcitonin Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Mediated by membrane receptors SOMATOSTATIN EFFECTS Cloned : sstr1 – sstr5 Logo Logo RECYCLED (resensitized) INTERNALIZATION Lysosome Endosome (dephosphorylation) In-111 DTPA D-Phe OC Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Normal human tissues SOMATOSTATIN RECEPTOR EXPRESSION High incidence and density in human neoplasias Non-endocrine Pituitary adenomas Non-neural cell tumors Pancreatic islet-cell tumors Lymphoma Gastroenteral NE tumors (carcinoids) Breast cancer Paragangliomas Renal-cell cancer Pheochromocytomas Hepatocellular cancer SCLC Prostate cancer Medullary thyroid cancer Sarcoma Gastric carcinoma Logo 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? Logo 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 Logo Servicio de Medicina Nuclear – Instituto Nacional de Cancerología Logo Servicio de Medicina Nuclear – Instituto Nacional de Cancerología 23-03-06 Logo 9-10-08 Servicio de Medicina Nuclear – Instituto Nacional de Cancerología D Phe - Cys - H - Ala - Gly - Cys - Lys - Asn - Phe - Phe Trp s DTrp s s s Lys Thr – Cys - OH - Cys - Ser - Thr - Phe - Tre (ol) Somatostatin -14 Octreotide Half-life < 3 min Half-life: 6 h In- - DTPA - D Phe - Cys - Phe 111 DTrp s s Lys Thr – Cys - Thr (ol) ['"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 In- GaTc-- - -DOTA HYNIC - D Phe - Cys - Tyr - DTPA - D Phe - Cys - Phe 9968m 111 DTrp DTrp s s s s Lys Lys Thr – Cys - Thr Thr – Cys - Thr (ol) (ol) 68Ga-DOTA-Tyr3-OC Affinity 9 : 1 111In-DTPA-OC 99mTc-HYNIC-TOC Affinity 3 : 1 DPhe - Cis - Tyr DTrp Affinity for sstr2 (DTPA o DOTA): s 14- to 17-fold >octreotide s 8- to10-fold >TOC Lys Thr - Cys - Thr Octreotate Higher affinity, higher rate of internalization, higher tumor uptake Logo Logo 99mTc- Hynic-Tyr3-Octreotide 111In-DTPAº-Phe1-Octreotide Nuclear Medicine Department – Instituto Nacional de Cancerología Logo 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 Logo 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 Logo Servicio de Medicina Nuclear – Instituto Nacional de Cancerología Logo Logo Logo Logo Physiologic vs pathologic gastric uptake Biodistribution in time Logo Logo Logo Spect corporal total: Logo Logo Logo Logo Servicio de Medicina Nuclear – Instituto Nacional de Cancerología Logo Servicio de Medicina Nuclear – Instituto Nacional de Cancerología Logo MOLECULAR IMAGING SPATIAL RESOLUTION vs MOLECULAR RESOLUTION CT/ MR Structural mmol PET/ SPECT mol Metabolism Sensitivity 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 Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs INDICATIONS • Search for primary tumor • Post surgical follow-up • Assess extent of disease • Screen for recurrences when • Assess treatment response. tumor markers are elevated • Select patients for radionuclide • Differential diagnosis between treatment NETs are space-occupying lesions • Radioguided surgery of small tumors/ confirmation of complete resection. Logo 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. Logo Logo Logo Logo Logo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Clinical Impact IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs Cost-benefit relationship Avoids unnecessary surgery Detects previously SPECT/CT undetected metastases 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 Logo 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 Logo 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 Logo 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 Logo 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 .
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