MOLECULAR IMAGING AND PEPTIDE RECEPTOR MOLECULAR

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MOLECULAR IMAGING AND PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRNT) OF NEUROENDOCRINE TUMORS: CURRENT STATE AND FUTURE PERSPECTIVES Professor Dr. Richard P. Baum Department of Nuclear Medicine , Center for PET/CT Zentralklinik Bad Berka, Germany [email protected] [DOTA0-d-Phe1-1-Nal3]-octreotide

DOTA-NOC

DOTA-OC

DOTA-TOC

A Annual lM Meeting ti off the th Czech C h Cooperative C ti Group G for f NETs NET (KSPNN) PRUHONICE, April 29, 2011

Summary 68Ge/Ga Generator ¾ Post-processing of 68Ge/68Ga radionuclide generators using cation exchange resin provides chemically and radiochemically pure 68Ga (97±2%) within 4 min ready for on-line labelling

¾ Highest chemical purity guarantees for high labeling and overall product yields (e.g. 68Ga-DOTA-conjugated octreotides) of 75±5% decay corrected ¾ Ready for injection – up to 10 patients per day can be studied easy handling in a nuclear medical environment easilyy to transfer to IAEA and other countries Significant step towards the routine medical use of the 68Ge/Ga generator

68Ga-DOTA-TOC

versus 111In In-DOTA-TOC DOTA TOC and 99mTc Tc-HYNIC-TOC HYNIC TOC Gabriel et al. J Nucl Med 2007; 48: 508-518

PET

SPECT

CT

Results (n=84 Patients - NET) Sensiti vity

97% (69/71)

52% (37/71)

61% (41/67)

Specifi p city

92% ((12/13))

92% ((12/13))

71% ((12/17))

Accu racy

96% ((81/84))

58% ((49/84))

63% ((53/84))

C bi d Use Combined U off PET and d CT provides id the th highest hi h t accuracy Das Bild k ann nicht angezeigt werden. Dieser Computer v erfügt möglicherweise über zu wenig A rbeitsspeicher, um das Bild zu öffnen, oder das Bild ist beschädigt. Starten Sie den Computer neu, und öffnen Sie dann erneut die Datei. Wenn weiterhin das rote x angezeigt wird, müssen Sie das Bild möglicherweise löschen und dann erneut einfügen.

Univ.-Klinik für Nuklearmedizin

Affinity profiles (IC50) for human sst 2–5 receptors C Compound d

h 2 hsst2

h 3 hsst3

h 4 hsst4

h 5 hsst5

SS-28

2.5±0.3

5.7±0.6

4.2±0.3

3.7±0.4

IInIII-DOTA-NOC DOTA NOC

2 9±0 1 2.9±0.1

8±2

227±18

11 2±3 5 11.2±3.5

YIII-DOTA-NOC

3.3±0.2

26±1.9

>1,000

10.4±1.6

YIII-DOTA-TOC DOTA TOC

11 4±1 7 11.4±1.7

389±136

>10 000 >10,000

204±92

YIII-DOTA-OC

20±2.2

27±8

>1000

58±22

YIII-DOTA-LAN DOTA LAN

22 8±4 9 22.8±4.9

290±105

>1000

16 3±3 4 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

In Wahl R. (ed.): ( ) Principles and Practice of PET and PET/CT. Lippincott Williams & Wilkins, Philadelphia 2008 (p. 411-437).

Principles and Clinical Indications

Neuroendocrine Tumors (NET) – Diagnosis – Suspicion of NET Diagnostic Methods:

Typical T i l Symptoms S t ⇒ Diagnostic Pathways

Tests for Hormone Production

• (Endo-) Sonograpy • Endoscopy • MRI (CT S Scan)) • Somatostatin Receptor p PET/CT or Scintigraphy (SRS)

Imaging Procedures Th Therapy

Foregut

Midgut

Hindgut

Ga-68 SMS Receptor PET – Imaging Technique Images courtesy Heiner Bihl/Gabriele Pöpperl Klinik für Nuklearmedizin •Katharinen-Hospital, •Katharinen Hospital Stuttgart

0:20 p p.i. i

0:40 p p.i. i

1:00 p p.i. i

1:20 p p.i. i

1:40 p p.i. i

Injected activity: 1.5 MBq/kg (100-150 MBq, 3-4 mCi). 20 mg Lasix iv Start of acquisition: 60-90 min p.i. (30-180 min) Acquisition parameters: 2 min. per bed position Effective radiation dose: 3 mSv for 150 MBq 68Ga-DOTATOC (+CT) (Octreoscan® 12 mSv) Imaging characteristics: fast kinetics, fast renal clearance, high quality images with very low background high tumor uptake allows detection of very small lesions (3 to 5 mm) already 30 to 60 min. p.i. Image analysis: visual and quantitative (SUV) evaluation

Staging g g of NET by y Receptor-PET/CT ¾ Whole-body Whole body diagnosis („one-stop ( one stop shop“) shop ) ¾ Detection of unknown pprimaryy tumors (CUP) ( ) ¾ Evaluation of receptor status before PRRT or octreotide therapy

Indication

Re staging Follow-up Re-staging, Follow up e.g. in patients with rising tumor markers ((chromogranin, g , serotonin,, calcitonin,, glucagon) g g ) for detection of recurrence

Indication Patient evaluation before PRRT Receptor density – determined by receptor PET/CT: semiquantitative measurement by

SUV (Standardized Uptake Values)

Biodistribution Bi di t ib ti off th the G Ga-68 68 labeled l b l d somatostatin analog g DOTA-NOC in patients with neuroendocrine tumors: characterization of uptake in normal organs and tumor lesions. V. Prasad, V Prasad R.P. R P Baum Q J Nucl Med Mol Imaging 2010; 54:61-67

Ga-68 DOTA-NOC receptor PET/CT: SUV of primary tumors and metastases SUV in primary tumors and metastases (n = 1 1,400 400 studies)

Mean

Range

Primary tumors

19.2

8.2 – 109

Liver mets

20.9

3.3 - 105

Lymph node mets

9.5

4.2 – 152

Bone mets

13.6

3.0 – 20.4

Brain mets

12.3

4.6 – 17.2

Lung mets

2.3

1.6 – 5.6

Abdominal mets

14.8

5.8 – 34.1

Somatostatin receptor imaging using Ga-68 DOTA-NOC PET/CT gives accurate estimation of the receptor density density.

IRS Score for SSTR2A proportional to SUVmax and SUVmean

IRS Score for SSTR5 proportional to SUVmax

p<0.05

SSTR1 SSTR3

SSTR4

No significant correlation between the IRS score for SSTR1, SSTR3 and SSTR4 with the semiquantitative parameters p>0.05

Evaluation of therapy py response p Problems of using WHO or RECIST criteria: it i ¾

1 or 2-dimensions 2 dimensions only

¾

what is the amount of vital tumor?

Morphologic Response Criteria R Response CR

WHO Cancer 1981;47 207-14

complete disappearance of all disease manifestations in two observations at an interval of at least 4 weeks

PR

SD

PD

≥ 50 % decrease in tumor size

↑ or ↓ in tumor size of < 25 %

> 25 % increase in tumor lesions and/or appearance of new foci of tumor

Neither WHO nor RECIST criteria address tumor response with biological atand metabolic markers. least 30% RECIST J N CI 2000;92 ; 205–16

disappearance of all tumor lesions

decrease in the sum of longest diameter of tumor lesion

neither PR nor PD

at least 20 % increase in sum of the longest diameter of tumor lesion

Monitoring Response to Therapy

DESIST USE

RECIST

PERCIST

MOLECULAR RESPONSE PRECEDES MORPHOLOGY !

PET/CT in NET: Diagnostic Algorithm - Staging/CUP Functional Activity

Proliferation Index (Ki-67)

<20 %

>20 %

Ga-68-SMS (DOTA-TOC / DOTA-TATE / DOTA-NOC)

Negative

Present

F-18-FDG

F-18-DOPA F-18 DOPAMINE

Absent CgA / SYN +

In all patients, once (initially) Negative Positive Positive Negative FDG-PET/CT should be done

Positive

MDT / CDM* W+S OP PRRT TACE / SIRT Chemo

CgA / SYN -

Ga-68-SMS

*MDT = Multidisciplinary Tumor Board *CDM = Clincial Decision Making

PET/CT in NET: Diagnostic Algorithm - Restaging Therapy Response

Follow-Up

What is the clinical question to be answered? Status of patient (KPS, ECOG) Repeat p most relevant diagnostic modality

PET/CT, MRI, 4-phase CT

Decision on further therapeutic strategy

Use most relevant diagnostic modality

PET/CT (SMS, FDG, DOPA In addition when needed -Endoscopy -EUS EUS -Ultrasound -Fluoride PET/CT -…

Depending on the clinical question, primarily a whole-body diagnostic approch should be chosen.

Conclusion B Baum ett al. l R Recentt R Res C Cancer R Res. 170 170:225-42 225 42 (2008) Receptor PET/CT using Ga-68-labeled somatostatin analogues enables the molecular imaging of neuroendocrine tumors and their metastases with very high diagnostic sensitivity and specificity (n=4 788 Ga-68 PET/CT studies as of August 30, (n=4,788 30 2010) Advantages of Ga-68 SMS PET/CT: The Bad Berka Experience ¾ Quantitative, reproducible data (SUV) which can be used for selecting patients for PRRT and evaluation of therapy response ¾ Fast protocol (60-90 (60 90 min min.), ) patient friendly friendly, low radiation burden (10-12 (10 12 mSv) ¾ Flexibility, daily use, lower (!) cost than Octreotide scintigraphy ¾ A new gold standard for in vivo SMS receptor imaging Future perspectives: new peptides (e.g. for lung, breast, and prostate cancer), general nuclear medicine applications (e (e.g. g lung perfusion PET/CT for detection of PE, myocardial, bone, kidney, liver imaging, infection and many more).

Ga-68 Labeled Tracers in Clinical Use •

[68Ga-DOTA,Tyr3]octreotide (DOTA-TOC)



[68Ga-DOTA,1-Nal]octreotide (DOTA-NOC)*



[68Ga-DOTA]-TATE* Ga DOTA] TATE*



[68Ga-DOTA]-Lanreotide



[68Ga-DOTA]-Bombesin / AMBA AMBA* and DEMOBESIN DEMOBESIN*



[68Ga-DOTA]-D-Glu-Gastrin*



[68Ga Ga-DOTA]-F(ab’) O ] (ab )2-herceptin e cept



68Ga-Citrate



68Ga-DOTA-Tyrosin* y



68Ga-DOTA-HSA

Microspheres*



68Ga-NOTA-RGD

(angiogenesis)*



68Ga-BPAMP



68Ga-DOTA-



68Ga-DOTA-SHAL



…and many more to come!

(osteoblastic metastases)*

α-MSH (melanoma)* (lymphoma)*

*first use in Bad Berka

FUTURE DIRECTIONS F th generation Fourth ti peptides tid Antagonists of radiolabeled peptides may be superior to agonists Pansomatostatins: P t t ti t targeting ti a broader b d subtype and tumor spectrum M ltireceptor targeting Multireceptor

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MOLECULAR IMAGING AND PEPTIDE RECEPTOR MOLECULAR

MOLECULAR IMAGING AND PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRNT) OF NEUROENDOCRINE TUMORS: CURRENT STATE AND FUTURE PERSPECTIVES Professor Dr. Rich...

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