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19-11-2018
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PET/CT and PET/MR
Prof. Liselotte Højgaard
Clinical 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
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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
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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
RIGSHOSPITALET
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 man
Clinical 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
RIGSHOSPITALET
External LAP laser system
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Cervical cancer with metastases
Always whole-body examinations for radiotherapy
RIGSHOSPITALET
Radiotherapy and imaging
Radiotherapy planned by CT
If tumor is drawn too small possibilities for cure smaller
If tumor is drawn to large side-effects worse
PET 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”.
RIGSHOSPITALET
Advance PET scanner 1995
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After treatment 1. series
12 year old boy with Hodgkin’s lymphoma- before treatment
RIGSHOSPITALET
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
RIGSHOSPITALET
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
RIGSHOSPITALET
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
RIGSHOSPITALET
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.
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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
RIGSHOSPITALET
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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RIGSHOSPITALET
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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RIGSHOSPITALET
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
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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.
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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
RIGSHOSPITALET
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
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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.
RIGSHOSPITALET
“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.
