How to optimize diagnostic nuclear techniques?

Transcription

1 How to optimize diagnostic nuclear techniques? Prof. Dr. Christophe Deroose Nuclear Medicine - University Hospitals Leuven (UZ Leuven) Department of Imaging & Pathology KU Leuven Leuven Cancer Institute (LKI) Leuven, Belgium ESMO preceptorship on GI Neuro-endocrine tumors November 28 th and 29 th Leuven, Belgium Nuclear medicine in the era of hardwarebased fusion imaging 1

2 Era of hybrid imaging PET/CT SPECT/CT PET/MRI PET/MRI Molecular targets for GEP-NET imaging Receptor-based 18 F-DOPA 11 C-5-HTP 99m Tc-DMSA Phosphate metabolism Lysosome Serotonin pathway Catecholamine pathway IMT Peptide receptors Nucleus Passive diffusion Active transport Receptor/ligand internalisation LAT1 amino acid transporter Noradrenaline transporter NaPi co-transporter GLUT glucose transporter 123 I-IMT Secretory vesicle Secretory vesicle VMAT transporter Somatostatin receptor Glucose metabolism Bombesin receptor 18 F-Dopamine Metabolic tracers 123 I-MIBG 18 F-FDG CCK receptor VIP receptor GLP1 receptor Adapted from Koopmans, Crit Rev Oncol/Hem,

3 Classification of tracers available for NET imaging Peptide receptor based imaging Somatostatin receptor (SSR) Glucagon-like peptide 1 receptor (GLP-1) Metabolic tracers Fluorodeoxyglucose ( 18 F-FDG) Catecholamin and serotonergic precursors Catecholamines Proliferation tracers Fluorodeoxythymidine ( 18 F-FLT) Radiopharmaceutical For molecular imaging Attaches radionuclide to the vector Radionuclide: Linker Vector molecule: Emits externally detectable radiation upon decay Is responsible for a specific molecular interaction with the target (receptor, transporter, enzyme, ) 3

4 Peptide Receptors Receptor-based 99m Tc-DMSA Peptide receptors Passive diffusion Active transport Receptor/ligand internalisation 18 F-DOPA 11 C-5-HTP Phosphate metabolism Lysosome Serotonin pathway Catecholamine pathway IMT Nucleus LAT1 amino acid transporter Noradrenaline transporter NaPi co-transporter GLUT glucose transporter 123 I-IMT Secretory vesicle Secretory vesicle VMAT transporter Somatostatin receptor Glucose metabolism Bombesin receptor 18 F-Dopamine CCK receptor VIP receptor 123 I-MIBG 18 F-FDG GLP1 receptor Adapted from Koopmans, Crit Rev Oncol/Hem, 2009 Why peptides as radiopharmaceuticals? Peptide hormone receptors are excellent targets Expression on the cell surface, readily accesible Peptide hormones bind to these receptors with high affinity and specificity i.e. The receptor have a characteristic structure that can be recognized by an imaging agent Peptide hormones can serve as starting points for tracer development Receptor-ligand internalisation can lead to high uptake and retention 4

5 Somatostatin Receptor (SSTR) Seven transmembrane G-coupled receptor Six human subtypes SSTR1 SSTR2 (2A & 2B) SSTR3 SSTR4 SSTR5 Function secretions Endocrine Exocrine Cell growth Apoptosis Internalise upon agonist binding / recycle Weckbecker, 2003, Nat Rev Drug Disc Wase, JNM 2009 Overexpression of SSTR subtypes on NET 48% 86% 87% 50% cytoplasmic staining SSTR1 SSTR3 SSTR5 membrane bound SSTR2A 46% NET LN+ NET ileum NET pancreas Kaemerer, EJNM&MI,

6 SSTR overexpressing tumortypes NET Carcinoid: Thymus Bronchus Esophagus Stomach Small bowel Appendix Large bowel Unkown primary Pancreatic NET Gastrinoma Insulinoma Glucagonoma VIPoma ACTHoma Somatostinoma Non-functioning GEP-NET Other tumour entities Medullary thyroid carcinoma Neuroblastoma Pheochromocytoma Paraganglioma Small-Cell lung cancer Pituitary gland tumours Merkel cell tumours Menigeoma The somatostatin receptor as a molecular target Somatostatin receptor (SSTR) overexpressed in range of tumors Neuro-endocrine tumors Foregut Midgut Hindgut Bronchial carcinoid (typical and atypical) Small cell lung cancer Overexpression correlates with differentiation status No correlation with hormonal function of tumor SSR target of pharmacological therapy 6

7 Diagnostic agents for SSR Radionuclide + Chelator + Somatostatin analogue 111 Indium 99m Technetium Gallium 18 Fluorine DTPA DOTA NOTA HYNIC Octreotide Tyr 3 -octreotide Tyr 3 -octreotate Naph-octreotide DIAGNOSTIC COMBINATIONS: C In-DTPA-octreotide (Octreoscan ) Ga-DOTA,Tyr3-octreotide ( Ga-DOTATOC) Ga-DOTA,Tyr3-octreotate ( Ga-DOTATATE) Ga-DOTA, [Phe 1-1-Nal 3 ]-octreotide) ( Ga-DOTANOC) C9 SPECT P E T Vector molecule for SSR Somatostatin: plasma T 1/2 ~1 to 3 min Chemical modification needed Trp Lys Phe-Phe-Asn-Lys-Cys-Gly-Ala-H Thr- Phe-Thr- Ser-Cys-OH Trp Lys Phe-Cys- D Phe-H Thr- Cys-Thr(ol)-OH T 1/2 ~ 90 min Somatostatin (SS14), 14 amino acids Tyr 3- Octreotide, 8 amino acids (TOC) Octreotide, 8 amino acids Tyr 3- Octreoate, 8 amino acids (TATE) Trp Lys Tyr-Cys- D Phe-H Thr- Cys-Thr(ol)-OH Trp Lys Naϕ-Cys- D Phe-H Thr- Cys-Thr(ol)-OH Trp Lys Tyr-Cys- D Phe-H Thr- Cys-Thr-OH Naphtalene 3- Octreotide, 8 amino acids (NOC) 7

8 Dia 13 C9 Quid NOTA Christophe Deroose; C10 Afbeelding van de molecules? Christophe Deroose;

9 Linker Molecule - DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate Vector-linker combinations Breeman, 2011, Sem Nucl Med 8

10 Radioisotope Gallium- Gallium- ( Ga) Positron emitter Generator product (germanium-) No cyclotron needed for production ( 18 F) Metal Affinity profiles (IC 50 in nm) of SS analogues for human SSTR Very high High Moderate Low PAN 2,5 2 SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 2,5 d 2 2,3,5 Ga-DOTA-NOC >10, ± 0,4 40 ± ± ± 1.6 Wild et al, EJNM&MI, 2005:724 Reubi et al., Eur J Nucl Med. 2000;27:

11 Ga-DOTATOC: normal biodistribution SUV: 0-7 SUV: 0-16 High uptake: Spleen Adrenals Pituitary gland Kidney Bladder Moderate: Liver Pancreas (processus uncinatus) Bowel Inflammatory LN Low: Lung Brain Muscle Ga-DOTATOC: normal biodistribution 10

12 Ga-DOTATATE normal biodistribution: pituitary gland Ga-DOTATATE normal biodistribution: salivary glands 11

13 Ga-DOTATATE normal biodistribution: thyroid Ga-DOTATATE normal biodistribution: liver 12

14 Ga-DOTATATE normal biodistribution: spleen Ga-DOTATATE normal biodistribution: kidney 13

15 Ga-DOTATATE normal biodistribution: bowel Ga-DOTATOC normal biodistribution: adrenal 14

16 Ga-DOTATOC PET/CT is highly sensitive for small tumors MEN 1 Smallest lesion is 10 mm, but it is hotter than the spleen! Ga-DOTATATE: detection of small lesions LN: SUV max mm LN: SUV max mm LN: SUV max 35 Liver M+ 15

17 SRS ( 111 In-Octreotide) detects more NET lesions than FDG or MIBG n=96 SRS > FDG >MIBG Liver MIBG FDG Binderup, JNM, 2010 N=96 SRS ( 111 In-Octreotide) has higher sensitivity for NET than FDG or MIBG All NET subtypes, except colonic (FDG> 111 In-Octreotide) Total Sensitivity SRS: 89% MIBG: 52% FDG: 58% Binderup, JNM, 2010 For Ki67 >2% and 2%-15%, but not for >15% (FDG > Octreotide) 41% of grade 1 patients are positive on FDG! 16

18 ESMO guidelines for NET management Öberg, Ann Oncol, 2012 Follow-up of NET: timing of SRS SRS indicated during follow-up Resected tumor of indepent of N-status G1: Two yearly G2-G3: Yearly Non-resectable tumor indepent of N-status, liver metastases or other metastases G1: Two yearly G2-G3: Yearly At time of documentation novel lesions Timing to be adapted on an individual basis CT/MRI are complementary and allow to determine total tumor burden. Not indicated: benign insulinoma, type 1 gastric NET, rectal NET (complete resection), appendiceal NET (T1 &T2) Arnold, Neuroendocrinology 2009, ENETS Guidelines follow-up GEP-NET 17

19 SRS: Ga-peptide PET is superior to conventional scintigraphy Comparison 111 In-Octreotide, Ga-DOTATOC, CT (n=84) Sensitivity: Ga-DOTATOC 97% 111 In-Octreotide 52% CT 61% Better performance for small lesions in LN and bone Comparison 111 In-Octreotide, Ga-DOTATOC, CT Sensitivity: Gabriel, JNM, 2007 Ga-DOTATOC 100% 111 In-Octreotide 66% CT or MRI 73% Ga-DOTATOC finds more lesions in lung and bones Buchman, EJNM&MI, In-Octreotide vs. Ga-DOTATOC PET/CT SPECT 111 In-octreotide: Planar WB and SPECT 24 hour PI Ga-DOTATOC PET/CT: MIP and transverse section 30 min PI 18

20 Example of incremental lesion Ga-DOTATOC PET 111 In-octreotide SPECT Retroperitoneal lymph node aggregate: uptake intense on PET moderate on SPECT Retroperitoneal focal lymph node: strong PET uptake, but no uptake whatsoever on SPECT = incremental PET lesion Van Binnebeek, 2014, submitted 111 In-Octreotide vs. Ga-DOTATOC PET/CT: Number of incremental lesions on PET FOV SPECT vs SPECT 111 In-Octreotide detects incremental lesions Ga-DOTATOC detects incremental lesions N= In-octreotide SPECT lesions> Ga-DOTATOC PET FOV SPECT lesions 111 In-octreotide SPECT lesions= Ga-DOTATOC PET FOV SPECT lesions 111 In-octreotide SPECT lesions< Ga-DOTATOC PET FOV SPECT lesions Mean 95% CI Patients Mean: %CI from 4.8to Incremental lesions Ga minus incremental lesions 111 In-octreotide Van Binnebeek, 2013, manuscript in preparation 19

21 Ga-DOTATOC Ga-DOTATATE n=40 Lesions detected: SUV max Ga-DOTATOC: ± 14.7 Ga-DOTATATE: 254 (97%) 16.0 ± 10.8 Poepell, JNM, 2011 Very similar findings in Ga-DOTATOC vs Ga-DOTATATE Ga-DOTATOC DOTATO Ga-DOTATATE Poepell, JNM,

22 Ga-DOTANOC Wild et al, EJNM&MI, 2005:724 Ga-DOTATATE vs Ga-DOTANOC Normal Biodistribution Metastatic NET Ga-DOTANOC Ga-DOTATATE Ga-DOTANOC Ga-DOTATATE Kabasakal, EJNM&MI

23 Ga-DOTATATE vs Ga-DOTANOC n=20 Lesions detected: SUV max Ga-DOTANOC: 116 (89%) 24.5 ± 20.3 Ga-DOTATATE: ± 26.4 (p<0.001)) Kabasakal, EJNM&MI 2012 Ga-DOTATATE vs Ga-DOTANOC Ga-DOTANOC images only 116 of 130 (89 %) lesions. 14 lesions (11%) were missed Ga-DOTANOC Ga-DOTATATE Kabasakal, EJNM&MI

24 Clinical impact of Ga-DOTA-SSRL PET/CT vs 111 In-Octreotide Detection of smaller lesions Detection of lesions with only light to moderate SSR expression Detection of more lesions No change in therapy Change in therapy e.g.: Additional liver metastases change in liver directed therapy Extra-hepatic metastases (refrain from SIRS, refrain from livertx) One stop shop minutes door to door, including diagnostic CT ( 111 In-octreotide: 2 day procedure) Be careful with direct comparison between 111 In- Octreotide and Ga-DOTA-SSRL More lesions does not necessarily mean clinical progression! Imaging somatostatin receptor expression with SSTR antagonists Octreoscan (agonist) 111 In-DOTA-BASS (Antagonist) Wild, JNM

25 SSTR antagonists bind independently of receptor activation status Ga-NODAGA-JR11 aka OPS202: Fani, JNM

26 OPS202: Ga-SSRL antagonistic ligand with FDA orphan drug status Berlin, October 16, :21 PM CET: OctreoPharm Sciences GmbH, based in Berlin (Germany), announced today that the radiopharmaceutical company has received U.S. FDA orphan drug designation for its new radiotracer OPS202, based on a next generation antagonistic somatostatin analog for the management of neuroendocrine tumors. The FDA orphan drug designation is designed to promote drugs that demonstrate value for relatively rare diseases that affect fewer than 200,000 people in the U.S. January 2014: EMA orphan drug status Fluorine-18 labeled somatostatin analogues: Al 18 F 18 F-IMP466 Ga-IMP466 Without blocking Blocked Without blocking Laverman, JNM

27 Fluorine-18 labeled somatostatin analogues: direct labeling Without blocking Blocked Liu, JNM 2014 Pitfall: SSR expression on meningeoma ( Ga-DOTATATE) 26

28 Pitfall: inflammatory uptake in degenerative osteoarthritis ( Ga-DOTATATE) Pitfall: Accesorry spleen and probable intrapancreatic accessory spleen on Ga-DOTATOC 27

29 Intrapancreatic accesorry spleen mimicking a NET on 111 In-Octreotide CT SRS ( 111 In-Octreotide) MRI FDG-PET Suriano, Tumori 2011 Peptide Receptors Receptor-based 18 F-DOPA 11 C-5-HTP 99m Tc-DMSA Phosphate metabolism Lysosome Serotonin pathway Catecholamine pathway IMT Peptide receptors Nucleus Passive diffusion Active transport Receptor/ligand internalisation LAT1 amino acid transporter Noradrenaline transporter NaPi co-transporter GLUT glucose transporter 123 I-IMT Secretory vesicle Secretory vesicle VMAT transporter Somatostatin receptor Glucose metabolism Bombesin receptor 18 F-Dopamine CCK receptor VIP receptor 123 I-MIBG 18 F-FDG GLP1 receptor Adapted from Koopmans, Crit Rev Oncol/Hem,

30 Glucagon-like peptide 1 (GLP-1) ligands for SPECT Receptors for glucagon-like peptide 1 (GLP-1) are highly overexpressed in almost all insulinomas HE Autoradiography Blocked Autoradiography Reubi, EJNM&MI, 2003; Korner, JNM 2007 [Lys 40 (Ahx-DTPA- 111 In)NH 2 ]exendin-4 pre-clinically validated tracer (RIP-Tag mouse model) Wild, JNM 2006 Mouse SPECT/CT 100 nmol/l GLP Glucagon-like peptide 1 (GLP-1) ligands for SPECT 4 h PI 4 days PI SPECT/CT Man, 64 year Neuroglycopenia Endogenous hyperinsulinism T/B:5.8 T/B:13.4 Tumor Autoradiography Control Autoradiography SPECT/CT: small nodule between the duodenum and the superior mesenteric artery Wild, NEJM

31 Glucagon-like peptide 1 (GLP-1) ligands for SPECT SPECT/CT - 23 hours PI Tumor Autoradiography Control Autoradiography Woman, 31 year Endogenous hyperinsulinism Fainting EUS: suspicious lesion in the transition zone between the pancreatic body and tail SPECT/CT: insulinoma Wild, NEJM 2008 Glucose Metabolism 18 F-FDG 18 F-DOPA 11 C-5-HTP 99m Tc-DMSA Phosphate metabolism Lysosome Serotonin pathway Catecholamine pathway IMT Peptide receptors Nucleus Passive diffusion Active transport Receptor/ligand internalisation LAT1 amino acid transporter Noradrenaline transporter NaPi co-transporter GLUT glucose transporter 123 I-IMT Secretory vesicle Secretory vesicle VMAT transporter Somatostatin receptor Glucose metabolism Bombesin receptor 18 F-Dopamine CCK receptor VIP receptor 123 I-MIBG 18 F-FDG GLP1 receptor Adapted from Koopmans, Crit Rev Oncol/Hem,

32 18 F-FDG PET detects patients with poor prognosis PFS OS FDG - FDG - FDG + FDG + HR: 9.4 HR: 10.3 N=98 Sensitivity for FDG: 58% Determines biological properties Binderup, Clin Cancer Res, F-FDG PET detects patients with poor prognosis PFS OS 2%<Ki67<15% Ki67<2% 2%<Ki67<15% Ki67<2% Ki67>15% Ki67>15% FDG adds prognostic information in groups with low and moderate Ki67 (<2% and <15%) Binderup, Clin Cancer Res,

33 Role of 18 F-FDG PET/CT in patients treated with 177 Lu-DOTATATE for advanced differentiated NET ileal NET (grade 2, Ki-67 9 %) FDG - Ga-DOTATOC + Severi, EJNM&MI, 2013 Role of 18 F-FDG PET/CT in patients treated with 177 Lu-DOTATATE for advanced differentiated NET FDG + Ga-DOTATOC Lu-DOTATATE + Severi, EJNM&MI,

34 18 F-FDG PET in patients treated with 177 Lu-DOTATATE PRRT for differentiated NET FDG - FDG - FDG + Median PFS 32 vs 20 months Severi, EJNM&MI, 2013 Metabolic grading of NET with 18 F-FDG Tumor/Liver Ezzidin, JNM,

35 Metabolic grading of NET with 18 F-FDG mg1 mg2 mg3 Ki67:10% Ki67:1% Ki67:20% Ezzidin, JNM, 2014 Metabolic grading of NET with 18 F-FDG Pathological grading Metabolic grading Ezzidin, JNM,

36 FDG Take Home Messages SRS Sensitivity > 90% compared to conventional techniques Is part of standard management in a large fraction of NET patients Time of diagnosis During follow-up First choice in patients with grade 1 or 2 NET Can be useful in isolated tumor marker rise (chromogranin, 5-HIAA) 111 In-Octreotide is a good tracer (use of SPECT/CT strongly advised) Ga-DOTA-SSRL are the best tracers, should be used when available Pitfalls: other tumors (e.g. meningeoma), spleen, inflammation Antagonists and fluorine-18 labeled molecules next step First choice in patients with grade 3 NET Offers prognostic information in patients with grade 1 or 2 NET Metabolic grading in metastatic patients? Questions? Leuven City Hall 35