Download Imaging, including PET in NeuroEndocrine Tumors Imaging

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.