NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy

NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Dr. Augusto Llamas Olier Nuclear Medicine Department Instituto Nacional de Cancerología

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

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)

NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs Other radioligands [ 68 Ga-DOTA]-D-Phe 1 -Tyr 3 -Octreotide [ 68 Ga-DOTA]-Tyr 3 -Octreotate [ 90 Y-DOTA]-D-Phe 1 -Tyr 3 -Octreotide [ 177 Lu-DOTA ]-Tyr 3 -Octreotate [ 18 F]-L-dihydroxyphenylalanine [ 11 C]-5-hydroxytryptophan ( 68 Ga-DOTA TOC) ( 68 Ga-DOTA TATE) ( 90 Y-DOTA TOC) ( 177 Lu-DOTA TATE) ( 18 F-L-DOPA) ( 11 C-5-HTP)

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

NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy

NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Mediated by membrane receptors SOMATOSTATIN EFFECTS Cloned : sstr1 sstr5

RECYCLED (resensitized) INTERNALIZATION Lysosome Endosome (dephosphorylation) In-111 DTPA D-Phe OC

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

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?

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

Servicio de Medicina Nuclear Instituto Nacional de Cancerología

Servicio de Medicina Nuclear Instituto Nacional de Cancerología 23-03-06 Logo 9-10-08

H - Ala - Gly - Cys - Lys - Asn - Phe - Phe D Phe - Cys - OH - s s Cys - Ser - Thr - Phe - Tre Trp Lys s s Thr Cys - (ol) DTrp Somatostatin -14 Half-life < 3 min Half-life: 6 h Octreotide

In- 111 - DTPA - D Phe - Cys - s Phe DTrp s Lys Thr Cys - (ol) Thr ['"Indium-diethylene triamine pentaacetic acid -D-Phe 1 ] 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

- - DOTA HYNIC - D Phe - Cys - s Tyr DTrp Ga- Tc- 99m 68 In- 111 - DTPA - D Phe - Cys - s Phe DTrp s Lys s Lys Thr Cys - (ol) Thr Thr Cys - (ol) Thr 68 Ga-DOTA-Tyr 3 -OC 99m Tc-HYNIC-TOC Affinity 9 : 1 Affinity 3 : 1 111 In-DTPA-OC DPhe - Cis - Tyr Affinity for sstr2 (DTPA o DOTA): 14- to 17-fold >octreotide 8- to10-fold >TOC s s DTrp Lys Thr - Cys - Thr Higher affinity, higher rate of internalization, higher tumor uptake Octreotate

99m Tc- Hynic-Tyr 3 -Octreotide 111 In-DTPAº-Phe 1 -Octreotide Nuclear Medicine Department Instituto Nacional de Cancerología

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

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

Physiologic vs pathologic gastric uptake

Biodistribution in time Logo

Spect corporal total: Logo

Sensitivity Logo MOLECULAR IMAGING SPATIAL RESOLUTION vs MOLECULAR RESOLUTION mmol CT/ MR Structural mol PET/ SPECT Metabolism 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

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.

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.

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

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

NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy COMING UP Somatostatin analogs labelled with positron emitters [ 68 Ga-DOTAº,Tyr 3 ]Octreotide o [ 68 Ga-DOTAº,Tyr 3 ]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 68 Ga: produced in generators / easy labelling on a daily basis o 90 Y- and 177 Lu -labelled counterparts are used for therapy

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. [ 111 Indio-DTPAº, Phe 1 ] octreotide: current standard but not perfect 5. TOC and TATE: more affinity, higher internalization rate than octreotide

NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy CONCLUSIONS II 6. Same peptide for diagnosis and therapy 7. New standard: [ 68 Ga-DOTAº,Tyr 3 ] Octreotide or [ 68 Ga-DOTAº,Tyr 3 ] Octreotate