NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy · 2015. 9. 3. · Neuroendocrine tumors Heterogeneous group of neoplasias derived from NE cells of the diffuse endocrine

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NEUROENDOCRINE TUMORS

Somatostatin Receptor Scintigraphy

Dr. Augusto Llamas Olier

Nuclear Medicine Department

Instituto Nacional de Cancerología

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Neuroendocrine tumors

Heterogeneous group of neoplasias derived from NE cells of the diffuse

endocrine system.

Characterized by:

Having neurosecretory granules

Producing bioactive amines (serotonine, catecholamines, histamine) and

polypeptidic hormones (somatostatin, gastrin).



Basis of the clinical utility of radiolabelled specific ligands

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DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs

• I-131/I-123 Metaiodobencylguanidine (MIBG)

Cellular structures for amine uptake and storage

Prefered indications: pheocromocytoma (specif. 80-100%) and

neuroblastoma (specif. 84%).

Sensitivity: 36% - 85%

• Somatostatin analogs (SA)

Overexpression of receptors for regulatory peptides (i.e.,

somatostatin).

Sensitivity: 78% - 100% (Indium-111 DTPA –Octreotide)



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DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs

Other radioligands

• [68Ga-DOTA]-D-Phe1-Tyr3-Octreotide (68Ga-DOTA TOC)

• [68Ga-DOTA]-Tyr3-Octreotate (68Ga-DOTA TATE)

• [90Y-DOTA]-D-Phe1-Tyr3-Octreotide (90Y-DOTA TOC)

• [177Lu-DOTA ]-Tyr3-Octreotate (177Lu-DOTA TATE)

• [18F]-L-dihydroxyphenylalanine (18F-L-DOPA)

• [11C]-5-hydroxytryptophan (11C-5-HTP)



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SOMATOSTATIN

Peptide regulatory

CNS and peripheral tissues

Hypothalamus

Action:

Neurotransmitter

Hormonal effects:

Inhibitory peptide

GH

Insuline

Glucagon

Gastrin

Serotonin

Calcitonin

Other effects:

Antiproliferative

in tumors

Specific regulation

of immune responses



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Mediated by membrane receptors

Cloned : sstr1 – sstr5

SOMATOSTATIN EFFECTS



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INTERNALIZATION

Endosome

(dephosphorylation)

RECYCLED

(resensitized)

Lysosome

In-111 DTPA D-Phe OC

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SOMATOSTATIN RECEPTOR EXPRESSION

Normal human tissues

High incidence and density in human neoplasias

Non-endocrine

Non-neural cell tumors

Lymphoma

Breast cancer

Renal-cell cancer

Hepatocellular cancer

Prostate cancer

Sarcoma

Gastric carcinoma

Pituitary adenomas

Pancreatic islet-cell tumors

Gastroenteral NE tumors (carcinoids)

Paragangliomas

Pheochromocytomas

SCLC

Medullary thyroid cancer



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DOMINATING EXPRESSION OF sstr 2

Simultaneous expression of multiple subtypes of sstr

Prostate: sstr 1

Non-functioning pituitary adenomas: sstr3

Inhibitory, antiproliferative and apoptotic effects

Basis for the clinical application of SA

Human hypophysis ≠ sstr 4

~100% gastrinomas express sstr

10%-50% insulinomas express sstr

¿Tumors with dominant sstr 4 expression?



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The expression of somatostatin receptors

of tumor diseases

Sarcoidosis: active granulomas

Rheumatoid arthritis: synovial vessels

Intestinal inflammatory disease: vascular

Is not specific

Tumoral or peritumoral

Blood vessels

Immune cells

Contaminant normal cells



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Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

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Logo 23-03-06

9-10-08


Phe

Trp

Lys

Tre

Ala - Phe - Asn -

Thr - Ser -

H -

Phe -

Gly - Cys - Lys -

Cys - OH -

s

s DTrp

Somatostatin -14 Octreotide

Half-life < 3 min Half-life: 6 h

D Phe - Cys -

Cys - Thr –

(ol)

s

s

Phe

DTrp

Lys

Thr

D Phe - Cys -

Cys - Thr –

(ol)

s

s

- DTPA - In-

111

('"In-Pentetreotide) OctreoScan®; Mallinckrodt.

10 µg of peptide; 222 MBq (6 mCi); 5 MBq/kg (0,14 mCi/kg) of Indium-111

-diethylene triamine pentaacetic acid°-D-Phe1] octreotide ['"Indium

No adverse effects < 50 µg

Physical half-life: 2,83 days

Tyr

DTrp

Lys

Thr

D Phe - Cys -

Cys - Thr –

(ol)

s

s

- DOTA - Ga-

68

68Ga-DOTA-Tyr3-OC

Phe

DTrp

Lys

Thr

D Phe - Cys -

Cys - Thr –

(ol)

s

s

- DTPA - In-

111

111In-DTPA-OC

Tyr

Thr -

Lys

Thr

Cis -

Cys -

s

s

DPhe -

DTrp

Octreotate

99mTc-HYNIC-TOC

Tc-

99m - HYNIC -

Affinity 9 : 1

Affinity for sstr2 (DTPA o DOTA):

14- to 17-fold >octreotide

8- to10-fold >TOC

Affinity 3 : 1

Higher affinity, higher rate of internalization, higher tumor uptake

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99mTc- Hynic-Tyr3-Octreotide 111In-DTPAº-Phe1-Octreotide

Nuclear Medicine Department – Instituto Nacional de Cancerología

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Characteristics of a good scintigraphic scan

• Dose: 222 MBq (6 mCi, adults), 5 MBq/Kg (0.14 mCi/Kg, children)

• Spect should have enough counts per projection

• 6-fold contrast enhancement

• Separate overimposed structures

• Enhanced diagnostic sensitivity

• High-count static images are better than wholebody scanning

• Special projections and delayed imaging to solve doubts



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Characteristics of a good scintigraphic scan

• Dose: 222 MBq (6 mCi, adults), 5 MBq/Kg (0.14 mCi/Kg, children)

• Spect should have enough counts per projection

• 6-fold contrast enhancement

• Separate overimposed structures

• Enhanced diagnostic sensitivity

• High-count static images are better than wholebody scanning

• Special projections and delayed imaging to solve doubts SPECT/ CT



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Physiologic vs pathologic

gastric uptake

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Spect corporal total:

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SPATIAL RESOLUTION vs MOLECULAR RESOLUTION

CT/ MR Structural

Molecular resolution in the range of 2 nm

Sen

sitiv

ity

Spatial Resolution

mmol

mol

pmol

nmol

1 mm 5 mm 10 mm

PET/ SPECT Metabolism

Sensitivity: capacity to detect a molecular marker Courtesy: Dr. Diana Páez

MOLECULAR IMAGING

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• Post surgical follow-up

• Screen for recurrences when

tumor markers are elevated

• Differential diagnosis between

NETs are space-occupying lesions

• Radioguided surgery of small

tumors/ confirmation of complete

resection.

• Search for primary tumor

• Assess extent of disease

• Assess treatment response.

• Select patients for radionuclide

treatment

IN-111-OCTREOTIDE SCINTIGRAPHY FOR GEP-NETs

INDICATIONS



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• Post surgical follow-up

• Screen for recurrences when

tumor markers are elevated

• Differential diagnosis between

NETs are space-occupying lesions

• Radioguided surgery of small

tumors/ confirmation of complete

resection.


INDICATIONS



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Clinical Impact

Changes in management: 17% - 28%

Identification of new lesions

Clear up imaging findings

Avoids unnecessary surgery

Detects previously

undetected metastases

Cost-benefit relationship

SPECT/CT

Enhances image interpretation

Precise anatomical localization (32%)

Further changes in management (14%)



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COMING UP

Somatostatin analogs labelled with positron emitters

ADVANTAGES OVER GAMMA EMITTERS

• Better affinity for sstr2

• Bind to other sstr: useful for non sstr2-expressing tumors

• Better spatial and molecular resolution

(detectability: SPECT 1-2 cm / PET 0,5-1 cm)

• Combined anatomic and metabolic information: better sensitivity



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COMING UP

Somatostatin analogs labelled with positron emitters

[68Ga-DOTAº,Tyr3]Octreotide o [68Ga-DOTAº,Tyr3]Octreotate

• Multiple analogs in use with little infoormation exchange from center to

center.

• Will become the new standard in sstr-imaging

o High affinity for sstr2

o 68Ga: produced in generators / easy labelling on a daily basis

o90Y- and 177Lu -labelled counterparts are used for therapy



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1. SRS: to assess NETs and to identify candidates for

metabolic therapies

CONCLUSIONS I

5. TOC and TATE: more affinity, higher internalization rate than octreotide

2. Tumor uptake: depends on affinity for sstr2 and rate of internalization

3. Small changes in peptide structure, chelating agents, radiometal

will enhace affinity and internalization rate.

4. [111Indio-DTPAº, Phe1] octreotide: current standard but not perfect



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6. Same peptide for diagnosis and therapy

CONCLUSIONS II

7. New standard: [68Ga-DOTAº,Tyr3] Octreotide or

[68Ga-DOTAº,Tyr3] Octreotate



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NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy · 2015. 9. 3. · Neuroendocrine tumors Heterogeneous group of neoplasias derived from NE cells of the diffuse endocrine