radiopharmaceuticals in oncology imaging · a brief overview… 12/1/2017 2 targets ... ‐ cells...

12/1/2017

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Radiopharmaceuticals in oncology imaging

Dr Emmanuel DeshayesMontpellier Cancer InstituteFRANCE IAEA WorkShop, November 2017

[email protected]

18F‐Estradiol ?18F‐Choline ?18F‐DOPA ?18F‐Na ?18F‐FDG ?

Radiopharmaceuticals in oncology imaging

Dr Emmanuel DeshayesMontpellier Cancer InstituteFRANCE 27 November 2017

A brief overview…

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Targets

‐Receptors‐DNA‐Proteins‐Metabolism pathways…

Radiotracers

‐ Peptides‐ mAbs/Fragments‐ Cells

RadioIsotopes

For diagnostic imaging

Beta + emitters18F, 64Cu, 15O, 68Ga, …

PET/CT

Gamma emitters111In, 99mTc, …

SPECT/CT

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Targets

‐Receptors‐DNA‐Proteins‐Metabolism pathways…

Radiotracers

‐ Peptides‐ mAbs/Fragments‐ Cells

RadioIsotopes

For diagnostic imaging

Beta + emitters18F, 64Cu, 15O, 68Ga, …

PET/CT

Gamma emitters111In, 99mTc, …

SPECT/CT

BIOLOGY

PHYSICS & INSTRUMENTATIONS

D Hanahan and RA Weinberg (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

Cancer development is a complex mechanism

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Alam et al. 2015

In oncology, radiotracers can target a lot of different pathways

Molecular Imaging in oncology

• Metabolism– Glucose– Cell membrane– Proteins– Bone

• Tumor specific agents• Proliferation• Angiogenesis• Apoptosis• Vascularization• Hypoxia

Hans‐JurgenWester, AACR

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Molecular Imaging in oncology



18F‐FDG18F‐CHOLINE

68Ga‐DOTATOC68Ga‐PSMA

PET

SPECT (111In, 99mTc, 123I)

PET Radioisotopes

Physicochemical properties must fit biological properties of the radiolabeled

tracers

Positrons Emitters T½ (min)

18F 11015O 211C 2013N 10124I 604864Cu 76889Zr 468068Ga 67,8

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PET Radioisotopes

Physicochemical properties must fit biological properties of the radiolabeled

tracers

Positrons Emitters T½ (min)

18F 11015O 211C 2013N 10124I 604864Cu 76889Zr 468068Ga 67,8

• Produced by a cyclotron by bombarding oxygen 18enriched water with protons

• Half‐life: 110 min

• The most communly used PET isotope

Fluorine‐18

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• « on site » availability

• Germanium‐68/Gallium‐68 generators

• Relatively short half‐life, 68 min, adapted to “small”molecules (peptides, fragments…)

Gallium‐68

68Ge/68Ga

Glucose metabolism



Hans‐JurgenWester, AACR18F‐Fluorodesoxyglucose

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18F‐Fluorodesoxyglucose 18F‐FDG• Most commonly used PET/CT radiotracer

• Increased glucose metabolism in tumor cells (Wharburg effect)

• FDG is a substrate for hexokinase

• Tumor cells: Increase in number & activity of glucose transporters (GLUT1, GLUT3…) and hexokinase

• FDG trapped intracellularly

Glucose m

etabolism

• Staging of cancer

• Evaluation of an indeterminate lesion

• Assessing response to therapy

• Evaluation of suspected disease recurrence, relapse and/or residual disease

• Guide a biopsy

• Occult primary lesion

• Prior to surgery (confirm unicity of lesions)

18F‐FDG: Wide range of indications

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• Before injection• Check Contraindications

• Fasting (4‐6 hours)

• Strict rest at least 45 minutes before injection

• Glycaemia

• Injection IV (activities depends on PET devices)

• Images acquisition• 1 hour post injection

• Void bladder

Boellaard, 2015, European Journal of Nuclear Medicine and Molecular Imaging

18F‐FDG Physiological Distribution

• Brain

• Myocardium (variable)

• Urinary tract (excretion)

• Liver: low uptake

• Gastrointestinal Tract (variable activity)

PET CT Fusion

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Glycemia

G= 0.9 g/lG= 2.4 g/l

Fasting

Glycemia

G= 0.9 g/lG= 2.4 g/l

Fasting

Hyperglycemia Hyperinsulinemia

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Interval injection/acquisition

Zhuang et al; JNM 2001: 1412‐1417 Shankar et al. JNM 2006

Standardization : 60 minutes (+/‐10%)

Granulomatosis (sarcoidosis)

18F‐FDG PET/CT is not a specific « Imaging of Cancer », but reflects glucose consumption

18F‐FDG Limitations

• False Positive Results

Benign processes that can show 18F‐FDG uptake

‐ Neoplastic lesions‐ Granulation tissue (e.g. wound healing), ‐ Infections‐ Other inflammatory processes

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18F‐FDG PET/CT is not a specific « Imaging of Cancer », but reflects glucose consumption

18F‐FDG Limitations

• False Negative Results

‐ Small size‐ Some histological types not FDG

avid:‐ Indolent lymphomas‐ bronchioloalveolar

carcinomas‐ Mucinous tumors‐ Prostate cancer‐ Neuroendocrine tumors

(well differentiated)

S Uybico, Radiographics 2010

18F‐FDG PET/CT in a patient with bone metastasis from breast cancer

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Cell membrane metabolism



Hans‐JurgenWester, AACR18F‐CHOLINE, 11C‐CHOLINE

18F‐Fluorométhylcholine, 18F‐FluoroEthylcholine, 11C‐Choline

CellMembranMetabolism

• In vivo evaluation of choline kinase activity

• Choline is a precursor of membrane phospholipids, incorporated via choline kinase by phosphorylation

• Increase in choline phosphorylation in some tumors

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18F/11C‐Choline Physiological Distribution

KidneysLiver

Salivary glands

Urinary tract excretion

Pancreas

Slight uptake in bone marrow

18F‐Fluorométhylcholine

Prostate Cancer

Hepatocarcinoma

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Proteins metabolism



Hans‐JurgenWester, AACR18F‐FET, 11C‐MET, 18F‐DOPA

Physiological distribution:

striatum, kidneys, pancreas, liver,

gallbladder, biliary tract, esophagus, myocardium and

duodenum. Adrenal glands may be faintly

visible

18F‐Fluoro‐L‐DOPA

FDOPA is taken up via an amino acidtransporter, decarboxylated into[18F]fluorodopamine by aromaticL‐amino acid decarboxylase, andconcentrated in intracellularvesicles.

D.Taieb Endocrine Reviews 2014; P.Santhanam, Clinical Endoc. 2014

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18F‐Fluoro‐L‐DOPA

• Pheochromocytomas and paragangliomas: staging, restaging, follow‐up

• Carcinoid tumors: detection of primary lesions, staging

• Medullary thyroid cancer

18F‐Ethyl‐Tyrosine• Artificial amino acid taken up into upregulated tumor cells

• Brain Tumors: • Grading (high grade/low grade)

• Distinction recurrence/ necrosis

• Dose painting (IMRT)

V. Dunet, JNM, 2012

Dhermain et al. Lancet 2010

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Bone metabolism



Hans‐JurgenWester, AACR18F‐Na, 99mTc‐HDP, 99mTc‐HMDP, …

Bone Scan (99mTc‐HDP)

18F‐Na PET

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Tumor ‘Specific’ Agents (receptor expression)



Hans‐JurgenWester, AACR89Zr‐Traztuzumab, 68Ga‐DOTATOC, 68Ga‐PSMA…

TumorSp

ecificagents (receptorexpression)

Prostate cancer: PSMA

Maurer, Eiber, Schwaiger, Gschwend, 2016, Nature Reviews Urology

18F‐CHOLINE68Ga‐PSMA‐11

Afshar‐Oromieh, Babich, Kratochwil, Giesel, Eisenhut, Kopka, Haberkorn, 2016, Journal of Nuclear Medicine

Prostate Specific Membran Antigen

68Ga‐PSMA: higher sensitivity & specificity than 18F‐CHOLINE

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TumorSp


Prostate cancer: GRP• Gastrin‐releasing peptide (GRP) receptors are overexpressed in prostate cancer and may be targeted by 68Ga‐labelled bombesin analogues.

Minamimoto et al. JNM 2016; Mansi R, JNM, 2016

“68Ga‐PSMA‐11 and 68Ga‐RM2 had distinct biodistributionsin this small cohort of patients with biochemically recurrent

prostate cancer”

• Somatostatine receptors (SSR) are overexpressed in some tumors(ie Neuroendocrine Tumors)

• PET/CT (68Ga‐labeled peptides) have better diagnostic perf. over superiority 111In‐pentetreotide SPECT/CT

• Also of interest for PRRT (theranostic approach)

TumorSp


Somatostatin Receptor (SSR) Imaging

111In‐pentetreotide

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TumorSp


Estrogen Receptors: 18F‐EstradiolTumorSp


Estrogen Receptors: 18F‐Estradiol

Clinical Impact to be further investigated

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• Zirconium‐89: physical half‐life (3.3 days) suits well biological halflife of monoclonal antibodies (mAbs)

TumorSp


89Zr‐mAbs

Floor C. J. van de Watering, 2014

89Zr‐Trastuzumab: anti‐HER2 mAb

Proliferation



Hans‐JurgenWester, AACR18F‐FLT

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18F‐Fluoro‐L‐Thymidine (FLT)

“FLT PET may have a positive role to play inpredicting therapy response especially inbrain, lung, and breast cancers where goodcorrelation with Ki‐67 is observed”

Sanghera, IJNM, 2014V.R. Bollineni Eur J Cancer, 2016

Lamarca, CROH, 2016

Thymidine kinase I (TK1) activity proportional to cellular proliferation and

DNA synthesis

Angiogenesis



Hans‐JurgenWester, AACR18F‐Galacto‐RGD, 68Ga‐NODAGA‐RGD, etc…

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• Radiolabeled RGD peptides for Integrin αvβ3 imaging

Angiogenesis

Haojun Chen, Theranostics, 2016

• Radiolabeled RGD peptides for Integrin αvβ3 imaging

Angiogenesis

Haojun Chen, Theranostics, 2016

Clinical Impact ? To be further investigated

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Apoptosis



Hans‐JurgenWester, AACR99mTc‐Annexin‐V, 18F‐Annexin‐V

Apoptosis: programmed cell death

[18F]-Annexin V + Tc99m

99mTc‐Annexin‐V

Annexin‐V

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Hypoxia



Hans‐JurgenWester, AACR64Cu‐ ATSM, 18F‐FAZA, 18F‐MISO

HypoxiaImaging

99mTc nitro‐imidazole99mTc‐HL91123I‐IAZA

64Cu‐ ATSM18F‐FAZA18F‐MISO

• Prognostic marker (especially in H&N cancers)

Carlin, JNM, 2012Grimes, BJR, 2107

• Modification of radiotherapy planning (Boost with IMRT ?)

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THANK YOU FOR YOUR [email protected]

radiopharmaceuticals in oncology imaging · a brief overview… 12/1/2017 2 targets ... ‐ cells...

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