Nuclear Medicine Perspective for NETs and PRRT

Assistant Prof. Jolanta Kunikowska Nuclear Medicine Department, Medical University of Warsaw

Neuroendocrine tumors (NET)

Epidemiology

Modlin I , 2010

Epidemiology

Understand carcinoma

The Biology of Cancer (© Garland Science 2007)

Gerlinger M, NEJM 2012

CT- not enought

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.

cancer-related receptor expression

high density expression in cancer –low expression in normal tissue

stable overexpression during disease

Ideas for the receptor imaging

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

„magic bullet”

90Y177Lu

99mTc 68Ga

Metabolic pahtways in NET

Critical Reviews in Oncology/Hematology 71 (2009) 199–213

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

Somatostatin receptor scintigraphy

111In- octreotyd(Ocreoscan)

99mTc –tektrotyd PET/CT 68Ga DOTATATE

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

99mTc Tektrotyd vs 68Ga DOTATATE PET/CT

99m Tc Tektrotyd vs 68Ga DOTATATE

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

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

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.

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

68Ga DOTA-TATE 18FDG

18FDG?

Only in NEC?

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

18FDG vs 68Ga DOTATATE

Badanie PET/CT z 18FDG

SUV max >9

SUV max<9

SUV max >3

SUV max<3

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

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

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

Radiolabeled glukagon like pepide-1 analogs 68Ga-NOTA-exendin-4

Yaping Luo, Eur J Nucl Med Mol Imaging (2015) 42:531–532

Radiolabeled gastrin-like immunoreactive peptide CCK

CCK2 - MTC(>90%)- astrocytoma (65%) - stromal ovarian

cancers (100%)

CCK1- Neuroblastoma

and mengioma

68Ga DOTA-MG48

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

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

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

PRRT

90Y 90Y

90Y

PRRT no randomisation trialas,

but:

18 years of PRRTWell tolerated

Mild side- effects

Tumor shrinkageSymptoms relief

QoL improvementBiomarker reductionImpact on survival

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

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%

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

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

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

Side effects

http://ayayawae.wordpress.com/wallpaper/lightning-wallpaper/

Photograh by Larry W Smith /EPA

RADIONUCLIDE TARGETED THERAPY

CONVENTIONAL TREATMENTS

PRRT side effects

Nephrotoxicity grade 3 and 4 up to 3%Hematotoxicity up to 10 %, MDS 2 %

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

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

Quality of life

PRRT improve 36 % Khan 2011

Chemotherapy ?

Everolimus ?

Sunitynib increasing diarareaQol like placebo

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

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

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.

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

• α-emiters• PRRT – agonist vs antagonist SSTR• PRRT – cocktail of receptors• PRRT plus chemotherapy• PRRT plus kinase inhibitor

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

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

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

OS not reachedPFSSUVmax<9 48 monthsSUV max >9 26 months

FDG (+) SUV max median 7.2

Qualification to PRRT=

THERANOSTIC

SRS density68Ga-DOTATATEKi-67

18FDG Prognostic

factorOther tracer???

F RöschKernchemie Mainz

1898 Detection of Polonium

Nothing in life is to be feared, it is only to be understood.

Maria Skłodowska-Curie