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Somatostatin and its Receptors in Molecular Medicine for (gastro-entero-pancreatic neuro-) Endocrine Tumors Professor Dr. Richard P. Baum Chairman and Director, Dept. of Nuclear Medicine / PET−CT Center Zentralklinik Bad Berka, Germany [DOTA0-d-Phe1-1-Nal3]-octreotide DOTA-NOC DOTA-OC DOTA-TOC Ernest N. Morial Convention Center New Orleans, June 16, 2008 SNM 2008 Annual Meeting Educational Program Imaging, including PET in NeuroEndocrine Tumors GEP-NETs: > 40 Entities Considering: - Localization - functional activity - hereditery background Management of Neuroendocrine Tumors (NET) Multidisciplinary management of NET involves: – pathologists – gastroenterologists – endocrinologists – surgeons – oncologists – radiologists – nuclear medicine physicians Slides are not to be reproduced without permission of author. Multidisciplinary Neuroendocrine Tumor Center Zentralklinik Bad Berka Int. Medicine, Endocrinology, Gastroenterology, Oncology Abdominal and Endocrine Surgery Interventional Radiology Nuclear Medicine / PET-CT Center including a highly specialized nuclear medicine ward (20 beds) Neuroendocrine Tumors (NET) – Diagnosis – Susp. of NET Diagnostic Methods: Typical Symptoms ⇒ Diagnostic Pathways Tests for Hormone Production Imaging Procedures Therapy • (Endo-) Sonograpy • Endoscopy • MRI (CT Scan) • Somatostatin Receptor PET/CT or Scintigraphy (SRS) Foregut Midgut Hindgut Carcinoid Syndrome – Facial Flush IMAGING OF NET Courtesy Lisa Bodei et al. J Endocrinol Invest 2008 in press Slides are not to be reproduced without permission of author. RADIOLABELED OCTREOTIDE 1984 Autoradiography In vitro 1987 Scintigraphy 6 mCi In vivo 1992 Radionuclide Therapy 180 mCi In vivo Courtesy Marion de Jong, Rotterdam INCIDENCE OF SST-R: RESULTS OF IN VITRO STUDIES in vitro receptor status • • • • • • • Gastrinoma, Glucagonoma 100 % Insulinoma 72 % Paraganglioma 92 % MTC 38 % Carcinoid 88 % SCLC 57 % Pheochromocytoma 73 % are not to be reproduced Reubi et al. JNM 1999 adapted from Curr MedSlides Chem 2000 without permission of author. OctreoScan ® • 1992 - 2003: large number of clinical studies • effective in diagnosis and staging of tumors expressing SST-R 2 Slides are not to be reproduced without permission of author. Whole body 111In-pentetreotide scan and 99mTc-MDP bone scan in a patient with ileum NET. Note that the number of bone lesions shown by OctreoScan is much higher. Slides are not to be reproduced without permission of author. Sensitivity – OctreoScan vs. Ga-68 SMS PET Metastasizing bronchus carcinoid ANT(MIP) ANT POST In-111-DTPA-OC ANT POST (MIP) POST Tc-99m-DPD Ga-68-DOTA-TOC DOTA- D Phe1-Tyr3 Octreotide = DOTA-TOC Radiolabeling with Ga-67, Ga-68, Y-86, Y-90, In-111 and Lu-177 O HOOC N N HOOC N N NH -D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr(ol) DOTA-TOC COOH In vitro binding and animal studies (De Jong 1997, 1998) : ¾ high uptake and retention in SST-R positive organs and tumours in rats ¾ higher binding affinity for SST-R 2, and SST-R 5 than OctreoScan ® Targeted Therapy Peptide Receptor Radionuclide Therapy (PRRT) Otte et. al. Eur J Nucl Med, 1997; G. Paganelli et al., Cancer Biother. Pharm. 1999 Results from larger clinical trials available Receptor Scintigraphy Using the 99mTc-Labelled Somatostatin Analogue 2002 EDDA–TRICINE–HYNIC–TOC in 450 studies: Clinical Results In Different Tumor Types And Comparison with 111In DOTATOC During 90Y-DOTATOC Radioreceptor Therapy R.P. Baum, M. Schmücking, S. Fischer, C. Przetak, A. Niesen, H.R. Mäcke* EDDA-HYNIC-TRICINE-TOC O cyclic octopeptide D-Phe HN N NH2 Thr(ol) hydracino nicotin amide =complex function for Tc Cys Tyr D-Trp Cys Thr Lys D-Phe1-Tyr3-Octreotide HO OH H N HYNIC-TOC O HO coligand HO EDDA: Ethylenediamine-N-N`-diacetic acid TRICINE heterocyclic coligand 16 Advantages PET/CT Provides functional (PET) and anatomical (CT) information with highest accuary of image fusion Short acquisition times: ¾ CT-based attenuation correction ¾ 3D PET emission acquisition Quantitative (SUV) PET data PET and CT can be used indepently from each other Ga-68 DOTA-NOC Ga-68 Generator System Developed in close collaboration between Radiopharmacy PET/CT Center, Zentralklinik Bad Berka and Institute of Nuclear Chemistry Johannes Gutenberg-Universität, Mainz, Germany Zhernosekov K, Filosofov DV, Baum RP…. Rösch F J Nucl Med 2007 (Oct); 48:1741-48 First clinical studies 2004 68Ga-elution, purification and synthesis module Gallium-68 has the potential to become the Tc-99m for PET/CT! Prediction by R.P. Baum (2004) Affinity profiles (IC50) for human sst 2–5 receptors Compound hsst2 hsst3 hsst4 hsst5 SS-28 2.5±0.3 5.7±0.6 4.2±0.3 3.7±0.4 InIII-DOTA-NOC 2.9±0.1 8±2 227±18 11.2±3.5 YIII-DOTA-NOC 3.3±0.2 26±1.9 >1,000 10.4±1.6 YIII-DOTA-TOC 11.4±1.7 389±136 >10,000 204±92 YIII-DOTA-OC 20±2.2 27±8 >1000 58±22 YIII-DOTA-LAN 22.8±4.9 290±105 >1000 16.3±3.4 Wild D, Schmitt SJ, Ginj M, Mäcke HR, Bernard BF, Krenning E, de Jong M, Wenger S and Reubi J-C. Eur J Nucl Med Mol Imaging 2003;30:1338 * * Awarded the best scientific research paper in the EJNMMI in 2003 [DOTA0-d-Phe1-1-Nal3]-octreotide DOTA-NOC DOTA-OC DOTA-TOC Staging e.g. before PRRT, evaluation of receptor status, detection of unknown primary tumors (CUP syndrome) Slides are not to be reproduced without permission of author. NET SOMATOSTATIN RECEPTOR SCINTIGRAPHY (SRS) NET, SRS positive. Primary tumor in the duodenum and lymph node metastasis Slides are not to be reproduced without permission of author. SUV 22 GP-337156/05-08 Non-palpable, 6 mm NET of pancreas confirmed by surgery SA-345909/06-04 Non-functional NET with multiple liver metastases – CUP syndrome. Where is the primary? Indication Re-staging, Follow-up e.g. in patients with rising tumor markers (chromogranin, serotonin, calcitonin, glucagon) for detection of recurrence Slides are not to be reproduced without permission of author. Dept. of Nuclear Medicine/P.E.T. Center, Zentralklinik Bad Berka SMS-Receptor PET/CT: liver metastasis of NET Surgical specimen* Liver metastasis (Ø 1.5 cm, SUV 71) PET/CT and MRI image fusion coronal MRI Ga-68 DOTA-NOC PET/CT of a pancreatic neuroendocrine tumor detected by Ga-68 receptor PET/CT. Conventional imaging (including FDG PET, CT scan & ultrasound) had been normal! *Surgery performed by Prof. Dralle, UMC Halle Dept. of Nuclear Medicine/P.E.T. Center, Zentralklinik Bad Berka Follow-up Ga-68 DOTA-NOC PET/CT 2 years later: complete remission A B Liver metastasis CT normal Lymph node meta CT? C Bone metastasis Dept. of Nuclear Medicine/P.E.T. Center, Zentralklinik Bad Berka Osteoblastic metastasis: CT positive CT normal (meta 3 mm Ø in MRI) Cardiac metastases not detected on CT scan Pericardial metastases well appreciated on CT Indication Patient evaluation before PRRT Receptor density – determined by receptor PET/CT: semiquantitative measurement by SUV Slides are not to be reproduced without permission of author. Ga-68 DOTANOC Retrocrural LN-Mets SUV 152 Pancreas NET (07/2005), left resection of pancreas, exstirpation of liver metastasis (S2), splenectomy. NSE 39 ng/ml (<12.5). MRI retrocrural lesion, Ø 2.2 cm. LAR 20 mg 4 wks before. Retrocrural LN-Mets SUV 103 Ga-68 DOTATATE Antunes P, Ginj M, Zhang H, Waser B, Baum R P, Reubi J C, and Maecke H. Eur J Nucl Med Mol Imaging (2007) Evaluation of therapy response Problems of using WHO or RECIST criteria: - 1 or 2-dimensions only - what is the amount of vital tumor? Slides are not to be reproduced without permission of author. R.P. 302018/03-08+10 Morphologie before PRRT after 1st cycle after 2nd cycle relaps after 1 y PRRT – COMPLETE REMISSION AND RELAPS Receptor PET/CT using Ga-68 DOTA-NOC Measurement of receptor status and of tumor volume Ga-68 DOTA-NOC PET/CT before and after intra-arterial Peptide Receptor Radionuclide Therapy using Y-90 DOTA-TATE Before PRRT 4 mo after 1st. PRRT 3 mo after 2nd. PRRT Molecular tumor volume: 338 ml SUV: 16.6 before PRRT MTI = 5611 Molecular tumor volume: 274 ml SUV: 13.7 MTI = 3754 4 mo. after 1st PRRT Molecular tumor volume: 158 ml SUV: 15.2 3 mo. after 2nd PRRT MTI = 2402 MTI ml 6000 4000 2000 0 MTI = Molecular Tumor Index (MTV x SUV) Peptide receptor radionuclide therapy of inoperable neuroendocrine pancreatic carcinoma Molecular therapy response – Tumor volume measurements and quantification of SMS receptor density in vivo using Ga-68 DOTA-NOC PET/CT before and after PRRT Desist using only RECIST and use MORE Molecular and anatomic Response Measurements Slides are not to be reproduced without permission of author. Molecular Diagnostic Imaging of SMS-R positive tumors • NET of the intestine (foregut, midgut, hindgut) including bronchus carcinoid, GEP-NET • Meningioma • Aesthesioneuroblastoma • Medullary thyroid cancer (MTC) • Paraganglioma • Pheochromocytoma • Adrenal carcinoma • Thymus cancer • Glomus tumors • Merkel cell tumours (and many more….) Slides are not to be reproduced without permission of author. Extensive metastases of malignant pheochromocytoma / paraganglioma syndrome FG-336870/05-08 SRS- PET/CT - ‘Gold standard’ for paraganglioma diagnosis SUVmax 109 Ga-68 NOC F-18 FDG MRI Glomus tumor with skull invasionProgression after EBR (50 Gy) DG-341988/05-12 Conclusions: Ga-68 Receptor PET/CT The Bad Berka Experience Receptor PET/CT using the Ga-68-labeled somatostatin analogue DOTA-NOC enables the molecular imaging of neuroendocrine tumors and their metastases with very high diagnostic sensitivity and specificty (n=2,660 Ga-68 PET/CT studies as of June 12, 2008) Advantages: ¾ Semiquantitative, reproducible data (SUV) which can be used for selecting patients for PRRT and evaluation of therapy response ¾ Fast protocol (60-90 min.), patient friendly, low radiation burden (10-12 mSv) ¾ Flexibility, daily use, lower (!) cost than Octreotide scintigraphy ¾ A new gold standard for in vivo SMS receptor imaging Future studies will concentrate on other anti-cancer peptides (e.g. lung, breast, and prostate cancer) as well as on general nuclear medicine applications (e.g. lung perfusion PET/CT for detection of PE, bone imaging etc.). Other PET Radiopharmaceuticals for imaging neuroendocrine tumors ¾ F-18 FDG ¾ F-18 Fluordopa ¾ (C-11 HDDP) Slides are not to be reproduced without permission of author. Highly differentiated neuroendocrine tumor /carcinoma Ki-67 < 5% Ki-67 > 30% Courtesy M. Anlauf, Kiel Poorly differentiated neuroendocrine carcinoma Inverse flip flop phenomenon: FDG positive, receptor negative neuroendocrine tumor Patient not suitable for PRRT F-18 FDG Ga-68 DOTA-NOC SUVmax 8.3 SUVmax 15.9 PET/CT Center Zentralklinik Bad Berka [18F]DOPA and [11C]HTTP – Clinical Indications Uptake and decarboxylation of amine precursors of dopamine / serotonin • Diagnosis of well differentiated, serotonin positive GEP NET Montravers et al. J Nucl Med 2006 (SE: 93% vs. 25% in serotonin - GEP NET) Becherer et al. J Nucl Med 2004 (high sensitivity esp. for detection of bone & hepatic metastases) • Diagnosis of pheochromozytoma / paraganglioma / glomus tumors Hoegerle et al. Radiology 2002 Hoegerle et al. EJNMMI 2003 • Diagnosis of medullary thyroid ca. with elevated calcitonin levels Hoegerle et al. EJNMMI 2001 • Diagnosis of CT/MRI negative insulinomas • DD focal vs. diffuse congenital beta cell hyperplasia in children • Hardy OT et al. J Pediatrics 2007 F-18 DOPA PET/CT Medullaty thyroid cancer • Thyreoidectomy 2002 • Increase of calcitonin and CEA Courtesy of G. Pöpperl Klinik für Nuklearmedizin • Universität München LMU F-18 DOPA PET/CT Adrenal adenoma vs. pheochromocytoma adrenal adenoma pheochromocytoma Courtesy of G. Pöpperl Klinik für Nuklearmedizin • Universität München LMU F-18 Fluorodopa PET a b Diagnosis of focal (a) and diffuse (b) congenital hyperinsulinism Courtesy of A. Alavi University of Pennsylvania „Anyone who stops learning is old, whether at 20 or 80. Anyone who keeps learning stays young. The greatest thing in life is to keep your mind young.“ Henry Ford (1863 – 1947) Slides are not to be reproduced without permission of author.