nuclear medicine perspective for nets and prrt · nuclear medicine perspective for nets and prrt...
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Nuclear Medicine Perspective for NETs and PRRT
Assistant Prof. Jolanta Kunikowska Nuclear Medicine Department, Medical University of Warsaw
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Neuroendocrine tumors (NET)
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Epidemiology
Modlin I , 2010
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Epidemiology
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Understand carcinoma
The Biology of Cancer (© Garland Science 2007)
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Gerlinger M, NEJM 2012
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CT- not enought
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CT- not enought
THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy –The Bad Berka Experience Richard P. Baum and Harshad R. Kulkarni Theranostics. 2012; 2(5): 437–447.
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cancer-related receptor expression
high density expression in cancer –low expression in normal tissue
stable overexpression during disease
Ideas for the receptor imaging
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History of SRS and PRRT isolation SS
synthesis, 123I-octreotide
registration 111In Octreoscan
First therapy 111In Octreoscan
First therapy 90Y DOTATOC
First therapy 177Lu DOTATATE
First therapy 90Y/ 177Lu DOTATATE
1972198719931994199620002006
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„magic bullet”
90Y177Lu
99mTc 68Ga
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Metabolic pahtways in NET
Critical Reviews in Oncology/Hematology 71 (2009) 199–213
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Peptide receptors in NET
S-R: Sst1-sst5, VIP-R: VPAC1, VPAC2, CCK-R: CCK1, CCK2, Bombezyna: B1 (NMB), B2 (GRP), BB3, GLP1-R.
NMB – neuromedin GRP – gastrin releasing peptide GLP – glucagon-like peptide
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Somatostatin receptor scintigraphy
111In- octreotyd(Ocreoscan)
99mTc –tektrotyd PET/CT 68Ga DOTATATE
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Affinity to SSTR
Radiopharmaceutical SSTR 1 SSTR 2 SSTR 3 SSTR 4 SSTR 5
Ga68-DOTA-NOC >10000 1.9±0.4 40.0±5.8 260±74 7.2±1.6
Ga68-DOTA-TOC99mTc-Tektrotyd
>10000 2.5±0.5 613±140 >1000 73±21
Ga68-DOTA-TATE >10000 0.20±0.04 >1000 300±140 377±18
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99mTc Tektrotyd vs 68Ga DOTATATE PET/CT
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99m Tc Tektrotyd vs 68Ga DOTATATE
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68Ga DOTATOC PET in patients with negative 111 In Octreoscan
51 patients, 35 Octreoscan (-), 27 patients 68Ga DOTATATE PET positive, sensitivity 87%, specificity 100%
Srirajaskanthan JNM 2010;51;875-882
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Density of receptors SRS Krenning scale
= liver 2> liver 3> spleen/kidney 4
Density of receptors- SUVmax in PET/CTPuritary
glandAdrenalgland
Liver Kidney Spleen
SUV max 11±4.5 14±5.6 6.5±2.2 14.2±3.6 18.9±6.6
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Other somatostatine analogues
Levent Kabasakal, Eur J Nucl Med Mol Imaging 2012 Apr 20.
RESULTS: On visual evaluation both tracers produced equally excellent image quality and similar body distribution. The physiological uptake sites of pituitary and salivary glands showed higher uptake in (68)Ga-DOTATATE images. Liver and spleen uptake values were evaluated as equal. Both (68)Ga-DOTATATE and (68)Ga-DOTANOC were negative in 6 (30 %) patients and positive in 14 (70 %) patients. In (68)Ga-DOTANOC images only 116 of 130 (89 %) lesions could be defined and 14 lesions were missed because of lack of any uptake. SUV(max) values of lesions were significantly higher on (68)Ga-DOTATATE images.
CONCLUSION: Our study demonstrated that the images obtained by (68)Ga-DOTATATE and (68)Ga-DOTANOC have comparable diagnostic accuracy. However, (68)Ga-DOTATATE seems to have a higher lesion uptake and may have a potential advantage.
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Other somatostatine analogues
Damian Wild et all J Nucl Med 2013 vol. 54 no. 3 364-372 .
The lesion-based sensitivity of (68)Ga-DOTANOC PET was 93.5%, compared with 85.5% for (68)Ga-DOTATATE PET (P = 0.005). The better performance of (68)Ga-DOTANOC PET is attributed mainly to the significantly higher detection rate of liver metastases rather than tumor differentiation grade.
CONCLUSION:
The sst2,3,5-specific radiotracer (68)Ga-DOTANOC detected significantly more lesions than the sst2-specific radiotracer (68)Ga-DOTATATE in our patients with GEP-NETs. The clinical relevance of this finding has to be proven in larger studies.
68Ga-DOTATATE 68Ga-DOTANOC
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68Ga DOTA-TATE 18FDG
18FDG?
Only in NEC?
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18FDG vs 68Ga DOTATOC/TATE
G1/G2- 18FDG (+) 67%
G3 - 18FDG (+) 90%
G1 - 18FDG (+) 28%
G2 - 18FDG (+) 67%
Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors:Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT. Oh S, Prasad V, Lee DS, Baum RP. Int J Mol Imaging. 2011;2011:524130.
Own exeprience
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18FDG vs 68Ga DOTATATE
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Badanie PET/CT z 18FDG
SUV max >9
SUV max<9
SUV max >3
SUV max<3
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Do we need GLP-1 receptor targeting?
Tumor Somatostatin-R sst2
Glucagon-like Peptide-1-R GLP-1-R
incidence mean R-density (dpm/mg)
incidence mean R-density (dpm/mg)
1 Gastrointestinal carcinoid tumor
26/27 5’433 8/27 1’027
2 Insulinoma 18/26 3’807 25/27 8’1333 Gastrinoma 10/10 8’193 10/10 2’461
4 Bronchial carcinoid tumor
19/28 4’505 11/29 2’456
Reubi et al. Eur J Nucl Med 2003
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111 In- Radiolabeled glukagon like pepide-1 analogs
Example of GLP-1 receptor–positive and sst2 receptor–negative malignant insulinoma
Damian Wild, J Nucl Med July 1, 2011 vol. 52 no. 7 1073-1078
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Male K.B., 77- years olddouble insulinoma, one 9 mm and 2mm,lesions not visualized, distal resectionT/nT 3,4
[Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4
Anna Sowa-Staszczak Jagiellonian Univesity, Cracow
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Radiolabeled glukagon like pepide-1 analogs 68Ga-NOTA-exendin-4
Yaping Luo, Eur J Nucl Med Mol Imaging (2015) 42:531–532
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Radiolabeled gastrin-like immunoreactive peptide CCK
CCK2 - MTC(>90%)- astrocytoma (65%) - stromal ovarian
cancers (100%)
CCK1- Neuroblastoma
and mengioma
68Ga DOTA-MG48
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Diagnosis what now?before qualification to PRRT
HistopatologyG1, G2, G3, Ki- 67 <20 %TNM
Kidney function GFR >40 ml/min
Labolatory testHgB ≥ 10 g/dL ; WBC ≥ 2*109/L; PLT ≥ 90*109/L.
Karnofsky index ≥ 60.
Probability of life >3 months.
Ki-67
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What we must know before qualificationto PRRT
Imaging?- anatomy– contrast enhanced CT?- SSTR expression and density
PET/CT 68Ga DOTATATE orSRS 99mTc-tektrotyd?
- others?18FDG PET/CT?18F- DOPA PET/CT?
Understanding biology of tumorsbetter selection of patients
new strategy
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PRRT – choise of isotope
T 1/2 Energymax(MeV)
Range(mm)
Gamma
90 yttrium(90Y)
2.7 2.25 10 0 %
177 lutetium(177Lu)
6.7 0.497 2-4 6-10 %
Marion de Jong et al. J Nucl Med (46): 2005, suppl 1:13S-17S
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PRRT
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90Y 90Y
90Y
PRRT no randomisation trialas,
but:
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18 years of PRRTWell tolerated
Mild side- effects
Tumor shrinkageSymptoms relief
QoL improvementBiomarker reductionImpact on survival
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Response of treatment 90Y DOTA TOC PFS 25-36 months
OS 22-40 months 177Lu DOTA TATE PFS 33 months,
OS 46 months Kwekkenboon 2008
90Y /177Lu DOTA TATE PFS 29.4 monthsOS not reached Kunikowska 2011
OS 49.8 - 52.8 Everolimus PFS 11.0 months Yao 2011
Sunitynib PFS 11.4 months Raymond2011
Chemotherapy (Streptozocyna + doksorubicyna +5 FU) PFS 18 monthsOS 37 months Kouvaraki 2004
Temozolamid PFS 14.0 monthsOS 35 months Kulke 2009
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Response of treatment 90Y DOTA TOC PR/CR 8-33%
177Lu DOTA TATE PR/CR 36-46 %
90Y /177Lu DOTA TATE PR/CR 20 %
Chemotherapy (Streptozocyna + doksorubicyna +5 FU) PR/CR 39%
Everolimus PR/CR 5%
Sunitynib PR/CR 9%
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Results of PRRT
48 years old patient with unknow primary tumor.18 FDG PET/CT shown positive uptake in majority of metastases as well in 68Ga - DOTATATE
6 and 12 months after PRRT 68Ga DOTATATE shown regresion of liver metasteses, but after 18 months disease progression
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Results of PRRT
45 years old patient with colon cancer with peritoneal metastases.PET/CT with 18FDG shown positive uptake only in one focus, 68Ga - DOTATATE was positive in all metastases.
Following 68Ga DOTATATE after PRRT shown regresion of metasteses in 12 , 18 and 36months
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Results of PRRT
50 years old patient with gastrinoma.PET/CT with 18FDG was negative, 68Ga - DOTATATE was positive in all metastases.
Following 68Ga DOTATATE after PRRT shown regresion of metasteses, in 12, 18 and 36 months
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Side effects
http://ayayawae.wordpress.com/wallpaper/lightning-wallpaper/
Photograh by Larry W Smith /EPA
RADIONUCLIDE TARGETED THERAPY
CONVENTIONAL TREATMENTS
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PRRT side effects
Nephrotoxicity grade 3 and 4 up to 3%Hematotoxicity up to 10 %, MDS 2 %
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Maximum tolerated absorbed dose bone marrow 2 Gy kidneys 23 Gy
Impact of dosimetry
Mattias Sandström J Nucl Med January 1, 2013 vol. 54 no. 1 33-41
20 %< 4 doses 50 % > 4 doses
Absorbed dosed by bone marrow<0.2 Gy/cycle
Absorbed dosed by kidneyapp. 4.7 Gy/cycle
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Baseline renal function
Patients with inferior renal function, estimated by GFR before treatment, were exposed to significantly higher renal absorbed doses (p<0.01)
Patients with inferior renal function tended to develop a higher grade of haematological toxicity
Johanna Svensson Eur J Nucl Med Mol Imaging. 2015 Feb 6
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Quality of life
PRRT improve 36 % Khan 2011
Chemotherapy ?
Everolimus ?
Sunitynib increasing diarareaQol like placebo
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Results based on 18FDG - OS
The median overall survival (OS) time in both groups was not reach (p = 0.03)
OS from the diagnosis time18FDG (+) 92.2 months 18FDG(-) 156.2 months
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Results based on 18FDG – PFS
18FDG(+) 24.6 months 18FDG(-) 58.5 months (p <0.5).
Severi S Eur J Nucl Med Mol Imaging (2013) 40:881–888
18FDG(+) 20 months18FDG(-) 32 months
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Results of PRRT based on SUVmax68Ga-DOTANOC
Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT Sowon Oh, 1 Vikas Prasad, 2 Dong Soo Lee, 1 and R. P. Baum 2 ,* Int J Mol Imaging. 2011; 2011: 524130.
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Results based on receptor density (SUV)
32 old patient with pancreatic NET
18FDG PET/CT – positive in pancreas tumor68Ga - DOTATATE
pancreas tumor SUV max 73 liver metastases SUV max >20
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• α-emiters• PRRT – agonist vs antagonist SSTR• PRRT – cocktail of receptors• PRRT plus chemotherapy• PRRT plus kinase inhibitor
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Intraartelial α-emiter PRRT
C. Kratochwil, Eur J Nucl Med Mol Imaging (2014) 41:2106- 2119
Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC were treated with an intraarterialinfusion of 213 Bi-DOTATOC
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Agonist vs antagonist• Strong internalization
• Low number of sites
• No internalization• High stability• High number of sites
HUMAN 4-12 SSTR2 sites more for antagonist
Cescato R,J Nucl Med. 2011 Dec;52(12):1886-90 JC Reubi
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CONCLUSION:The study suggests that the use of a cocktail of 3 radioligands binding to somatostatin receptors, GLP-1 receptors and GIP receptors would allow detecting virtually all NET and labeling them homogeneously in vivo, representing a significant improvement for imaging and therapy in NET.
Reubi JC, Waser B1J Nucl Med. 2015 Feb 19.
Triple peptide receptor targeting in vitro allows detection of all
tested GUT and bronchial NETs
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OS not reachedPFSSUVmax<9 48 monthsSUV max >9 26 months
FDG (+) SUV max median 7.2
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Qualification to PRRT=
THERANOSTIC
SRS density68Ga-DOTATATEKi-67
18FDG Prognostic
factorOther tracer???
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F RöschKernchemie Mainz
1898 Detection of Polonium
Nothing in life is to be feared, it is only to be understood.
Maria Skłodowska-Curie