PET-CT beeldvorming Nieuwe mogelijkheden en toepassingen Sigrid Stroobants, UZA
Outline • Principe van PET/CT en nieuwe mogelijkheden • FDG-PET – FDG als tumor tracer – Indicaties • • • •
Staging Recidieven Therapie evaluatie Radiotherapie planning
• “Beyond FDG”
PET/CT METHODOLOGIE
Nucleaire Geneeskunde beeldvorming met radioactieve tracers RADIOFARMACON
“KOUD ” DEEL
RADIOACTIEVE LABEL
bepaalt de plaats van opname
bepaalt de detecteerbaarheid
Tracer of speurstof
Radioisotoop/-nuclide
Verschillende beeldvormingstechnieken SPECT
PET
+ -
511 KeV
-
+ -
+
0
0
+
+
0
0
+ + -
-
-
0 0
-
511 KeV 180o
2 fotonen (hoek 180°) Hoge energie Electronische collimatie Steeds tomografisch
1 foton Lagere energie collimator Planair + tomografisch
CT
Hybride systemen
CT
PET
PET technique – Historical Overview 1995 Stand alone PET 10 cm FOV AC Ge-68 ring source FBP 3 h/ scan
1998
2003
2010
PET-CT (128 slice) 22 cm FOV AC CT based HD-TOF <15 min/scan
Time of Flight (TOF) PET Conventional PET
TOF PET
TOF- PET No TOF
TOF
WB-PET in 10 min met lagere FDG dosis (7 mSv) Hogere throughput (tot 25 patiënten per dag)
State of the art CT scanner • Mogelijkheid tot uitvoeren diagnostisch CT onderzoek met per oraal en IV contrast • Joint reading van de beelden door NG en RX Hogere accuraatheid One-stop shop
State of the art CT scanner Aandacht voor stralingsbelasting! – Aanvullende Diagnostische CT enkel zo klinisch geindiceerd Veneuze faze CT Ikv N- en M- staging of voor beoordeling therapie effecten
– Bevat alle nieuwe tools voor reductie van stralingsbelasting Dose Care Iteratieve reconstructie
170 mAs@120kV DRL 24 mGy
FBP
+ASIR
FPB
110 mAs@120kV DRL 7 mGy
IRIS
FDG-PET IN DE ONCOLOGIE
FDG uptake in tumour cells Normal Cell Glucose 6-phosphatase
Neoplastic Cell 18FDG
FDG-6-P
FDG-6-P Glycolytic pathway
Glucose 6-phosphatase
Hexokinase Glycolytic
Hexokinase
pathway
G6P Glucose 6-phosphatase
G6P
D-glucose
Glucose 6-phosphatase
(Inflammatory Cells)
FDG-PET in Lung Cancer
T4 (2 lesions)
T1 + fibrotic mass
Effect serum glucose level Glyc 220 mg%
Glyc 70 mg%
551125m109
Effect of fasting and serum glucose level
6h fasting nl glycemia
Non-fasting nl glycemia
6h fasting glycemia 226 mg%
6h fasting glucose-infusion nl glycemia
Use of PET in oncology
FDG avidity of tumours • FDG uptake ~ proliferation capacity histopathologic grade aggressive tumours
high FDG uptake
slow growing tumours
low FDG uptake
FDG avidity Variability within same histological subtype: example DLBCL
Use of PET in oncology
Sensitivity •
depending on FDG avidity of the tumour cells
•
critical mass of metabolic active cells is required > 8-10 mm
OK
< 0.5 cm
no indication for PET
Fong et al.
52 resected hepatic M+ in colorectal Ca > 1cm = 85% vs < 1cm = 25%
• depending on tracer uptake in surrounding tissue e.g. low sensitivity for brain metatstasis
Use of PET in Oncology
Specificity •
uptake in macrophages – inflammatory/infectious lesions
•
uptake in benign lesions
•
Fysiological uptake in normal structures mimicking cancer – Muscle uptake – Brown fat – Gut, urinary system
Luteal cyste
Baseline
811022m176
End of R/
FDG-PET VOOR TNM STAGING
PET for TNM staging • T = tumor • Size • Local extension
• N= Nodes • Absence N0 • Presence N1-N3
• M= Metastasis • Absence M0 • Presence M1
Limited additional value ? agressiveness
Important additional value Detection of small-sized metastatic LN Exclusion of enlarged inflammatory LN Resolution problem no minimal disease adjacent to tumour Correct localization Most important additional value PET=whole body imaging focused on tumour Not for brain DD CT equivocal lesions Correct localization, DD fysiologic uptake
RIZIV Terugbetaling in Belgie • Lymphoma • Long • Slokdarm • Ovarium • Pancreas • Melanoma
PET for N-staging in NSCLC pT1N0
P
P
pT1N2
DD malignant vs benign LN pT2N0
pT1N0
pT2N3
Definition of PET+LN Hellwig et al, JNM 2007 Retrospective analysis of 95 patients with suspected NSCLC and underwent mediastinoscopy and had PET prior to surgery Comparison of visual analysis (> mediastinal BG) and SUV max LN
PET for N-staging Impact of integrated PET-CT
pT2N1
Esophageal cancer - Nodal staging of primary disease Flamen et al. JCO 2000 CT + EUS
N=74
PET
p-value
Sensitivity N 1-2 M +Ly
15/18 (83%) 6/13 (46%)
4/18 (22%) 10/13 (77%)
p=0.002 NS
5/11 (45%) 20/29 (69%)
10/11 (91%) 26/29 (90%)
NS (p=0.07) p=0.04
20/29 (69%) 26/42 (62%)
14/29 (48%) 36/42 (86%)
NS (p=0.07) p=0.009
Specificity N 1-2 M +Ly
Accuracy N 1-2 M +Ly
PET/CT pitfalls
PET/CT for Nodal staging in Cervixca Kitajima et al, Eur Radiol. 2009
False negative lymph node of 9 mm
PET for M-Staging C
A
B
PET/CT in EC‐ M‐Staging
FDG-PET VOOR DETECTIE RECIDIEVEN
PET in Oncology - Recurrent disease • Detection of tumor less accurate on CT after treatment - disturbed anatomy - no discrimination between viable tissue/fibrose • Importance of accurate staging prior to resurgery • PET currently reimbursed for – – – – –
head and neck cancer lymphoma colorectal cancer ovarian cancer Brain
CRC Local recurrence
1 month later APO +
CRC liver recurrences
Vogel et al, Cancer Imaging 2005 Patient with prior RFA (upper arrow) and liver resection for liver metastasis of colon carcinoma. Both CT (a) and MRI (c) are difficult to interpret The PET image (b) clearly shows a recurrent liver metastasis (lower arrow), which could be localized only after image fusion with MRI (d). This permitted guided locoregional therapy
CRC – Liver M Spatz et al, Int J Colorectal Dis 2010 Retrospective analysis in 34 ptn with liverM+ of CRC scheduled for surgery Correlation of imaging with hostopatholgy Imaging: 16 slice MDCT or 1.5 T MR ; 16 slice PET/CT and IUS
PET/CT for detection of Peritoneal carcinomatosis Pfannenberg et al, Annals of Surg Oncol 2009
FDG-PET VOOR THERAPIE EVALUATIE
Response assessment to cancer treatment
Baseline
Baseline
Patient 1
Patient 2
After 8x CHOP CRu
After 8x CHOP PR
New PET-CT response criteria Baseline
Courtesy of Juweid Malik
End of therapy
New Cheson Guidelines for end of treatment evaluation Cheson et al, JCO 1999 and Cheson et al, JCO 2007
IWG criteria -
PET
IWC+PET criteria
Complete remission (CR): No more lesions visible Complete remission unconfirmed (CRu): reduction >75%
+
CT
Partial remission (PR): reduction >50% Stable disease (SD): reduction <50% Progressive disease (PD): new lesion or >50% increase
Exception New lesion < 1.5 cm and PET – is also PD
New Cheson Criteria in NHL Brepoels, Stroobants et al., Leuk Lymphoma 2007;48:1522-1530
Materials and methods
Data Spaepen, JCO 2000, 69 pts with NHL after CHOP like therapy Revision of PET and CT images following IWG and new Cheson criteria Correlation with updated outcome
2 analyses
Potentially curable lymphoma Considered incurable lymphoma
New Cheson criteria in Aggressive NHL Brepoels, Stroobants et al., Leuk Lymphoma 2007;48:1522-1530 PFS agressive lymphoma IWC+PET Cumulative Proportion Surviving (Kaplan-Meier) Relapse Censored
PFS aggressive lymphoma by IWC Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored
IWG
New Cheson
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
CR SD
0.6 0.5
CRu PR
0.4 0.3
0.5 0.4 0.3
0.2
0.2
0.1
0.1
PD
0.0
500
1000
PD
0.0
-0.1 0
CR
0.6
1500
2000 Time
2500
3000
3500
-0.1 4000
0
PR
SD 500
1000
1500
2000
2500
3000
Time
Data Spaepen, JCO 2000, PET after first line R/ Updated and IWC + PET response in 55 pts with routinely FDG-avid and potentially curable (aggressive) NHL
3500
4000
New Cheson criteria in Indolent NHL Brepoels, Stroobants et al., Leuk Lymphoma 2007;48:1522-1530 IWG
Data Spaepen, JCO 2000 , PET after first line R/ Updated and IWC + PET response in 14 pts with not-routinely FDG-avid and incurable NHL (8 FL, 4 MCL, 2 MZL)
New Cheson
N=260
PET in DLBCL after more intensified treatment or in combination with Retuximab Haioun et al, Blood 2005 Induction Chemotherapy (4 cycles) (R)-CHOP/3w (> 60y) R-ACVPB/2w ACVBP/ACE
Baseline
PET 2 N=90
Consolidation/salvage Treatment R-ACVPB High Dose + AutoSTx
PET 4 N=80
Comparison of PET results after 2 and 4 cycles 13 patients PET2 positive became PET4 negative Patients that were PET negative after 2 remained PET negative after 4
SPECIFIC CRITERIA for MID-TREATMENT
FDG-PET response in SOLID tumors • Solid tumors are rarely cured with chemotherapy only, so even in good responders residual uptake remains – Quantitative PET data are necessary – Standardization – Definition of threshold values
• Often multimodality treatment is used – timing of PET scans – underestimation of response due to inflammation (RTx) – no detection of minimal residual disease
no ”standard” PET or PET-CT response criteria available EORTC Response criteria (> 25% decrease)= definition of “non-response”
FDG-PET response in Breast Cancer Rouseau et al, Journal of Clinical Oncology, 2006 64 patients with LABC, treated with IC (5FU, Docetaxel, Epirubicin)
Correlation PET response and pathological response
FDG-PET response in Breast Cancer Rouseau et al, Journal of Clinical Oncology, 2006 64 patients with LABC, treated with IC (5FU, Docetaxel, Epirubicin)
Sataloff regression grade A Total or near total B more than 50% regression C less than 50% regression D No regression
PET as a surrogate marker of OUTCOME Hoekstra, C. J. et al. J Clin Oncol 2005; 23:8362-8370 PET Chemo
PET Chemo
Pall RT
PET Chemo
PD
CR/PR/SD Surgery / RT
ΔSUV >35% ΔSUV <35% After 1 cycle
ΔSUV <60% After3 cycle
ΔSUV >60%
PET as a surrogate marker of OUTCOME Hoekstra, C. J. et al. J Clin Oncol 2005; 23:8362-8370
CR/PR &SUV ≤ 3.0
CR/PR &SUV >3.0
MR/SD/PD &SUV ≤ 3.0 MR/SD/PD &SUV >3.0
MUNICON Trial Lordick et al. Lancet Oncology 2007
PET response in SOLID tumors Is targeted therapy different? • Major volume reductions are rare or occur late Effective dose max tolerated dose Functional imaging even more important • What to expect? Cell cycle or growth arrest > cell death – Reduction in FDG uptake less pronounced? – Proliferation markers more sensitive?
FLT - Principle of uptake TK 1
Cancer: TK1 (x3-x4) degradation ↓
‘metabolic trapping’
TK 1
PET in GIST treated with Imatinib CT d0
CT 4w
CT 24w PET d0
PET d8 190604v096
PET in GIST treated with Imatinib Stroobants et al. Eur J Cancer 2003 PFS according PET response 8 days after start of treatment Time to treatment failure
Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored 1,0 0,9
Cumulative Proportion Surviving
0,8 0,7 0,6
PET CR
0,5 0,4 0,3 0,2 0,1
P < 0.001
0,0
PET no CR
-0,1 0
100
200
300 Time
400
500
600
700
Imaging Response to Imatinib Partial resistance to Imatinib
1 week after withdrawal of Imatinib
FDG uptake in GIST cell line 882 after Imatinib Hans Prenen et al, Am Journal of Biochem and Biotech 2005: 95-102, 2005
Hexokinase Hexokinase
FDG
FDG
FDG-P
Glut-transporter
FDG uptake
Glut-TR
FDG uptake after Glivec Cullinane et al, Cancer Research 2005 Hematological cell with mutant cKIT Glivec sensitive (V560) or resistant mutation (V816) Glucose uptake
Cell viablility
FDG uptake in NSCLC cell lines during Gefitinib Su H, et al Clin Cancer Res. 2006 Oct. L858R mutation
WT
FLT
PI3kinase pathway and glycolysis
Thompson et al, JCO 2004
Future: Combining with tracers for other metabolic pathways (Glutaminolysis)?
FDG-PET BIJ RADIOTHERAPIEPLANNING
PET for M-Staging Mac Manus et al. Int J. Rad Oncol Biol Phys. 2002
PET in Radiotherapy planning Target volume delineation No FDG uptake in atelectasis
Courtesy of Prof Baum, Bad Berka, Germany
PET in Radiotherapy planning Target volume delineation Display window setting affects lesion size
Courtesy of Humm
PET in RT planning
PET BEYOND FDG
Aanmaak van PET tracers- Cyclotron • Radioisotopen van natuurlijke elementen 11C, 13N, 15O, 18F
Kort halfleven – aanmaak “on-site” Sterke gelijkenis met natuurlijk vookomende moleculen in het menselijke lichaam Inbouw in bestanddelen zonder aantasting van de kenmerken hiervan: “fysiologische labelling”
Aanmaak van PET tracers - Radiofarmacie
- Snelle synthese - Kennis van metabolisme
PET beyond FDG •
Nieuwe tracers voor klinisch gebruik
F-18- Fluoro ethyl tyrosine (FET) - Hersentumoren F-18 Fallypride of C11- Raclopride – Parkinson en Psychiatrie PET- amyloid tracers – vroegtijdig opsporen van Alzheimer Dementie 0-15 water – activatiestudies en doorbloeding hart (Choline PET) – prostaatkanker FLT-PET – respons evaluatie Hypoxie-PET –radiotherapieplanning
• Experimentele tracers (proefdieronderzoek) Vroegtijdige therapie respons bij tumoren Neurodegeneratief lijden en epilepsie Geneesmiddelen onderzoek (in samenwerking met Janssen Pharmaceutica)
PET in hersentumoren – F18- FET • Inschatten van maligniteitsgraad van de tumor • DD tumorrecidief vs radionecrose na RT
Choline-PET Prostate Cancer
FLT-PET • Mantel cell lymphoma R/mTOR inhibitor
FLT d0
FLT d+7
Vroegtijdige detectie van de Ziekte van Alzheimer
Amyloid PET
Atrofie (hippocampus)
Beeldvorming voor onderzoek naar neuroplasticiteit Water PET na verschillende soorten geluiden (stilte, praten, natuurgeluiden) bij 1. Normale patienten 2. Dove patienten met cochleair implantaat met goede spraakherkenning 3. Dove patienten met cochleair implantaat met slechte spraakherkenning
Stilte vs natuurgeluiden vs praten
Molecular Imaging in geneesmiddelen onderzoek
Microdosing Voor biodistributie
Drug binding voor dosis bepaling
Preclinical Imaging
kidneys lymphoma
Day 0
Day 6
Day 9
Day 13
SC inoculation of 5.106 DAUDI cells (human Burkitt lymphoma cell line)
Day 16
Imaging labo for kleine proefdieren
MICA & Bio Imaging Lab
x3 x2
Nucleaire Geneeskunde@UZA/UA - Anno 2011
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