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PET/CT and PET/MR

Prof. Liselotte HøjgaardClinical Physiology, Nuclear Medicine & PET

Rigshospitalet, University of Copenhagen & Technical University of Denmark Chair Danish National Research Foundation

10. November 2016 DTU

RIGSHOSPITALET

University hospital 100.000 patients per year discharged, 140.000 operations 12.000 staff, 250 ph.d.s, 2000 publications, 120 professorer Founded in 1757 as the first hospital in the Nordic countries with the aim

of curing patients and doing research

Rigshospitalet

RIGSHOSPITALET

130.000 studies/year, 160 publikations, 200 staf, 25 Ph.d., 5 professors,

2 cyklotrons, 7 PET/CT, PET/MRI, micro-PET and MRI, ½ bio. dk.kr.

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Chair of The Danish National Research Foundation

Board member Novo Nordisk foundation

Board member Karolinska Instituttet, Stockholm

Mitglied Die Robert Bosch Stiftung, Germany

Affiliations

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RIGSHOSPITALET

X-rays were described for the first time by Wilhelm Conrad Röntgen, Würzburg, in 1895.

1044 papers about X-rays in medicine were published in 1896.

The first X-ray machine Copenhagen 1896

RIGSHOSPITALET

Nuclear Medicine was developed inCopenhagen by Georg de Hevesy & NielsBohr and published in 1935.

Hevesy won the Nobel Prize in 1943 for thetracer technique.

Nuclear Medicine was born in Copenhagen

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PET/CT December 2001

RIGSHOSPITALET

Diagnostic imaging in cancer

Ultrasound CT MR

PET/CT

DiagnosisStaging – how widespread is the disease ?Treatment effectRelapse – has the disease reappearedPlanning of surgery and radiation therapy

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Many diseases, many methods, which to choose ?

Ultrasound CT MR

PET/CT

Diagnostic accuracy – sensitivity and specificityPrizeSide effectsAvailability Cost effectiveness> 10.000 articles

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2001 first PET/CT scanners2002 first abstracts.2003 first paper New Engl J Med2004 first JNM supplement2008 5.000 papers on PET in oncology2009 first randomized paper PET/CT2011 first PET/MRI2014 PET/MRI with spin lab2016 PET/MRI routine for patientswith brain cancer and dementia

The rapid spread of PET/CT

RIGSHOSPITALET

PET/CT-indications 2018

35.000 publications on PET

Dementia, brain tumors, Parkinson

Heart - flow and metabolisme

Onkology: staging, treatment effect,relapse, control, RTP- and OP-planning

RIGSHOSPITALET

PET/CT with FDG is integrated in Danishroutine patient work up ”Kræftpakkerne”

- Lung cancer- Cervical and ovarian cancer- Lymphoma- Head & Neck- Malignant melanoma

PET/CT as first line imaging

On the basis of 12.500 publications: Loft et al 2007 Gyn Oncol, Hutchings et al 2006 Blood, Risum et al gynecol Oncol 2007. Fischer 2009 New Engl J Med

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Normal cells use glucose

GLU

FDG

Glut1 &3

GLU GLU-6-phosphate

CO2+H20

FDG FDG-6-phosphate

hexokinase

FDG fluoro-deoxy-glucose

RIGSHOSPITALET

Cancer cells use a lot of glucose

GLU

FDG

Glut1 &3

GLU GLU-6-phosphate

CO2+H20

FDG FDG-6-phosphate

Metabolic trapping

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Radioisotope Half-life (min)18F 109.811C 20.413N 9.9615O 2.05

FDG: F-18 flouro-deoxy-glucose

RIGSHOSPITALET

Cyklotrons for isotope production

PET – positron emission tomografi

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Radiochemistry Unit with lead hot cells

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PET tracers Use

[F-18] FDG Onkology[F-18] Altanserin 5-HT2A receptors[C-11] CUMI-101 5-HT1A receptors[C-11] DASB Serotonin transporter[C-11] Flumazenil Central benzodiazepin receptor[C-11] PIB beta-amyloid plaques[C-11] SB207145 5-HT4 receptors[O-15] H2O Brain CBF[N-13] NH3 Heart flow[F-18] FLT Cell proliferation[Cu-64] ATSM Hypoxia[Ga-68] DOTATOC Somatostatin receptors[Ga-68] ABY-025 Affibody/HER2 ekspression[F-18] FET Brain tumors

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”PET - The fastest growing medical technology ever ”

High sensitity and specificity, and game changer for 30 % !

Positron tracer F-18 FDG

Patient injection

PET scanning combined with CT

Interpretation by NM & radiologist

RIGSHOSPITALET

PET research

Basic research – cyclotron isotopes, radiochemistry tracers, scanner hardware and new math algorithms Translational – from lab to clinical patients in animal and manClinical research – diagnosis, treatment evaluation, relapse, radiation therapy planning

New isotopes, new tracers, new hardware & software, physiology, patophysiology, new drugs, new methods • non commercial • private-public partnership • industry driven

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PET/CT in cervical cancer

Metastatic lymph nodes:

•Pelvis

•Para-aortal

•Inguinal

•Mediastinum

•Neck

•Omentum

RH: Dr. Annika Loft & Dr. Anne Kiil Berthelsen

RIGSHOSPITALET

PET/CT and lung cancer

Preoperative staging of lung cancer with combined PET/CT. Randomized study on PET/CT and lung cancer staging. N= 189, Conventional or same + PET/CT.

Relative risk reduction for a futile thoracotomy 51 %.

Fischer & Højgaard, New Engl J Med 2009;2,361:32-9

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Cost effectiveness analysis:

Full health care sector perspective by Health Economist Outcome parameter: Numbers needed to treat (PET/CT scans) to avoid futile operation = 5.

Excluding costs due to co-morbidity PET/CT was cost effective with savings 900 € per patient.

With full analysis incremental cost 4.000 € for patients in PET/CT group, as 4 patients in PET group were extremely expensive.

So , dependent on which model you use results can either be a bargain or very expensive

Eur J Nucl Med 2011

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• Models have assumptions

• They may be wrong

• Could change conclusion to the opposite

• Systems are dynamic

• Costs and gains may change

Method problems:

PET the first diagnostic imaging method evaluated so meticilously

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PET/ CT scans are interpreted by a nuclear medicine specialist and a radiologist together- also for radiotherapy planningN= 1.000 per year as part of clinical routine

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External LAP laser system

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Cervical cancer with metastases

Always whole-body examinations for radiotherapy

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Radiotherapy and imaging

Radiotherapy planned by CTIf tumor is drawn too small possibilities for cure smallerIf tumor is drawn to large side-effects worsePET and MRI to improve methodology

CT FDG-PET MRI Treatment plan

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Dose painting from FDG-PET

Head & neck cancer: Preliminary results show that relapse is seen in the original PET+ part of the tumor, so that part should have higher dose

PET+ part given higher dose without increase in hramful dose to healthy tissue.

PET+ part tailor made therapy using local voxel intensity values: ”Dose painting by numbers”.

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Advance PET scanner 1995

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After treatment 1. series

12 year old boy with Hodgkin’s lymphoma- before treatment

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PET/CT for planning of radiation therapy

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3.000 børn/år

RIGSHOSPITALET

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Børneriget – målet er verdens bedste børnehospital

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Healthy

Parkinson’s Disease

18F-FE-PE2I DaT PET

Hippocampal Volume

T1 MRI

18F-FET PET

Recurrent Glioblastoma

Recurrence?

Alzheimer’s Disease

Prof. Ian Law

18F-FDG PET/MR

Klinisk praksis til hverdag

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Oline Vinter OlesenPhD, MSc (Eng. Medicine and Technology)Founder & CTO, TracInnovationsSenior Researcher, DTU Compute & RH

Bevægelseskorrektion med nyudviklet, patenteret system

World’s first

Structured light surface scanner with invisible light

Markerless tracking for MR & PET motion correction

RH, 2015

correcteduncorrected

Yale, 2011

correcteduncorrected

RH/MGH, 2015

MGH/Harvard, 2014

DTU/RH, 2010

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Development of new tracers .

Early evaluation of new drugs for cancer treatment with molecular imaging using animal studies with PET/CT and PET/MR.

Translational from use in animal to man.

Cluster for molecular imaging

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Tumor

Cell proliferation

Tissue characteristics

Invasive phenotype

Apoptosis

HypoxiaAngiogenesis

Glycolytic activity

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Tumor

Ki67, MCM2 ..

Molecular markers

uPAR

Caspase-3, survivin ..

HIF-1, CAIX ..Integrinv3, VEGF ..

GLUT-1, HK1, HK2

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Tumor

18F-FLT

PET tracers

64Cu-DOTA-AE10568Ga-NOTA-AE105

18F-Annexin V

64Cu-ATSM18F-Galacto-RGD

18F-FDG

RIGSHOSPITALET

CT uPAR-PET uPAR-PET/CT

PET/CT-scanning can predict weather cancer wil metastasise

Professor Andreas Kjær

Scanning of prostate cancer

This patient’s tumor wil spread - uPAR is high. Cu-64 uPAR tracer is the isotope Cu-64 with the urokinase-receptor demonstrating invasiveness.

RIGSHOSPITALET

Prof. Andreas Kjaer et al.

PDOX GBM GBM

Ex vivo target validation

uPAR-PET/MRI of brain cancer – from mouse to man

RIGSHOSPITALET

CD8a+ PET

CD8 PET imaging predicts response to immune checkpoint inhibitor therapy in different cancer types

Prof. Andreas Kjaer et al.

CD8 PET

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Biograph mMR – the worlds first simultaneous, whole-body molecular MR

Copenhagen PET/MRI

• Simultaneous PET and MRI• From December 2011

RIGSHOSPITALET

Morphology, physiology & molecular imaging ……….in the same scanner …at the same time

MR

PET

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FDG-PET

MR: T2w

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Navn (Sidehoved/fod)Titel/beskrivelse (Sidehoved/fod)

FDG-PET PET/MR fusionMR: T1w MR: T2w

PET funktion og MR anatomi i columna

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Frontal sinus Skull base

Error:Our method

Error: Scanner

New optimization of PET/MR: RESOLUTE

VolumeBrianCSF Air Bone

New technique for PET/MR adjusts the reconstruction error. Also useable in children. Error now <1 % on PET-signal

Claes Ladefoged, cand.scient., ph.d.-studerende

Average 204 patients

RIGSHOSPITALET

Multi-center evaluation of 11 PET/MR-correction methods

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Why PET/ MR in children?

• Simultaneous PET and MR

• More precise co-registration and anatomical localisation

• Simultaneously acq. of quantitative dynamic PET og MR with tracers and I.V. contrast

• MR-based motion-correction

• Shorter time in scanner – perhaps less sedation

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Simultaneous in vivo 13C-MRI and FDG-PET

FDG-PET MRIFDG-PET [1-13C]Pyruvate [1-13C]Lactate

H.B. Gutte, A.E. Hansen et al.; to be presented at EANM 2014

tumormuscle

tumormuscle

• Generation of [1-13C]Lactate and uptake of FDG in tumor• Increased 13C-lactate production in tumor compared to muscle:

o 13C-lactate/13C-pyruvate ratio tumor : 0.29 o 13C-lactate/13C-pyruvate ratio muscle : 0.085

Eye tumors

and PET

Purohit et al, Insights Imaging 2016;7(1):43-68

+ Meibomian or sebaceoglandular carcinoma SGC. Lynch syndromeMuri-Torre, associated to internal cancers, PET/CT for staging ?

+

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PET/CT revealed a tumour in the right eye…and several metastases besides a primary tumour in the right lung. Confirmed by biopsy.

82 year old woman with painfull tumour at the lateral edge of the left orbita.

Previously a mouth SCC some years ago.

Biopsy of orbitas tumor -squamous cell carcinoma. Perhaps secondary.

PET/CT with tumour in the left lacrimal gland and no signs of dissemination.

Operation with orbita exeration.

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Meningioma cells express

Somatostatin Receptor II (SSTRII)

WHO grade III meningioma

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The DOTA PET tracers

Neuroendocrine tumors SSTR II binding.

Perhaps PET/MRI or PET/CT for

meningioma imaging - as biopsies ?

No larger comparative human studies.

PET Radiotracer 64Cu  68Ga ‐DOTA‐Tyr3‐octreotide 68Ga ‐DOTATOC68Ga ‐DOTA‐ D‐Phe1‐Tyr3‐octreotate 68Ga ‐DOTATATE68Ga ‐DOTA‐ 1‐Nal3‐octreotide 68Ga ‐DOTANOC

Pfeifer A et al. J Nucl Med. 2015;56:847-854.PET DOTATOCSPECT Octreotide

RIGSHOSPITALET

68Ga –DOTATOC in meningeoma

Suspected recurrence of meningeoma WHO Grade I and loss of vision on right eye. Previous

Resection x 2, metal clips due to perioperative arterial lesion.

MRI: artefact caused by clips . No obvious recurrence.

68Ga-DOTATOC: Binding to active tumor tissue infiltrating the right optic canal

Susceptibility artefact

MRI MRI & PET CT & PET

12 year old boy, previously well, swelling of the right

eye. MRI local hospital: proces in right orbita around

bulbus.

Normal vision. Biopsy: embryonal rhabdomyosarkoma.

WB FDG PET/CT for staging.

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PET/CT : Malignant looking proces in right orbita, extra ocular, no bone involvement and no dissemination.

Chemo- og proton therapy in Houston.

1 year later suspicion of relapse of the rhabdomyosarcoma in the right orbita at control MRI. Referred to WB FDG PET/CT for metabolism in tumor and dissemination ?

Malignant tumor medially in right orbita without signs of dissemination. Chemoterapy, VIT.

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PET/MR and PET/CT and genes and epigenetics and clinical and life style information:”Personalised medicine”

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Personalized Medicine

Paradigm shift with tailored

prevention, early diagnosis,

treatment based on genes and

epigenetics &

The deep phenotype with imaging.

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“If this does not help, please come again, and we find something else”

“Couldn’t I get the something else right away ?”

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Conclusion

PET/CT-scanning for the diagnosis of cancer is a powerful tool with high accuracy and it is ”game changer” for 30 % of patients. PET/MR for brain.

Research with molecular imaging with new tracers to improve diagnosis and thereby patient treatment.

Interdiciplinarity and convergence between research areas. AI with deep learning for betterImage acquisition and description.