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Uso della PET nella valutazione della risposta

Cagliari, 21 giugno 2008

Arturo ChitiMedicina Nucleare, Istituto Clinico Humanitas, Rozzano - Milano

arturo.chiti@humanitas.it

K3

K4

Hexokinase ↑↑↑↑↑↑↑↑

Glucose-6-phosphatase ↓↓↓↓

18FDG-1-P

Glycogen

18F-fru-6-P

Glycolysis

18FDG-6-phospho-glucono-lactone

HMPshunt

18FDG

K1

K2

18FDG 18FDG-6P

FDG – Uptake and Metabolism

Buerkle and Weber, Cancer Metastasis Rev, 2008

FDG compartment model

Young et al, Eur J Cancer 1999

EmissionTransmissionCalibration

Detection limit

Fischer et al. EJNM 2005

Monitoring therapy response

• Objective and standardized criteria• WHO

– Two perpendicular diameters, 50% decrease– Moertel CG, Hanley JA. Cancer 1976

• RECIST– Largest diameter, 30% decrease

• One definition of response may not beadequate for prediction of response in alltumor types

Limits of morphologic imaging

• Radiologic criteria– Reduction in tumor size may take time– Scar tissue and edema may mask tumor

regression

• Histopatologic criteria– Regression score– Close correlation with survival in some tumors– Not useful to modify treatment

Monitoring response with FDG PET

• Visual interpretation– Uptake is specific for viable tumor tissue – Associated with a poor prognosis

• Quantitative assessment– Baseline scan

– Tumor response– Technical issues

Interpreting FDG uptake

Young et al, Eur J Cancer 1999

Methods of Analysis

Qualitative

Quantitative

T/N ratio

SUV

Patlak plot

Non-linear regression

Standardized Uptake Value

• Single image

• No arterial input function required

• Plasma clearance is “normal”

• Steady state is reached

• Correction for plasma glucose level (?)

• Correction for:• body weight

• body surface area (?)

• lean body mass (?)

Standardized Uptake Value

BW

AA

SUVo

tissuecBW

,=

Ac,tissue: Activity concentration in a volume (tissue) of

interest (VOI)

Ao: injected activity

BW: body weight

Quantitative FDG measurement

• Acquisition time • Partial volume effects• Heterogeneous uptake• Image processing

– smoothing / noise• ROI definition

– Max value– Mean value

• Plasma glucose level• FDG is not glucose

0

1

2

3

4

5

6

0 20 40 60

PrePost

Common errors in SUV calculation

• Para-venous injection• Residual activity in syringe• No decay correction of activity• Incorrect cross-calibration

scanner/calibrator• Variable uptake time

Interpreting SUV differences

• Tumors with sufficient baseline activity• 20% changes can be considered

significant• Metabolic stunning• Clinical context• Correlation with outcome demonstrated in

some tumors

EORTC criteria

• Progressive metabolic disease (PMD)– SUV increase > 25%– Visible increase in extent > 20%– New lesions

• Stable metabolic disease (SMD)– SUV increase < 25% or decrease < 15%– No visible increase in extent

• Partial metabolic response (PMR)– SUV reduction > 15-25% after one cycle– SUV reduction > 25% after more than one cycle

• Complete metabolic response (CMR)– Complete resolution of FDG uptake

Young et al, Eur J Cancer 1999

When perform FDG PET ?

• Chemo-sensitivity• Chemo-resistance• Chemotherapy

– Flare phenomenom

• Radiotherapy– False positive ?

Assessment of tumor response

Weber and Wieder EJNMMI 2006

Chemo-sensitivity

Chemo-resistance

Complete Censored

Time

Cum

ulat

ive

Pro

port

ion

Sur

vivi

ng

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 200 400 600 800 1000 1200 1400 1600 1800

PFS

PET-

PET+

Time

Cum

ulat

ive

Pro

port

ion

Sur

vivi

ng

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 200 400 600 800 1000 1200 1400 1600 1800

OS

PET-

PET+

NHL - Early PET response

Spaepen et al,

Annals of Oncology, 2002

PET predicts TF and PFS in HL

Hutchings et al Blood 2006

Use of Positron Emission Tomography for Responseassessment of Lymphoma: Consensus of the imaging subcommittee of International Harmonization Project

in Lymphoma

Malik Juweid, Sigrid Stroobants, Otto Hoekstra, Felix Mottaghy, Markus Dietlein,

Ali Guermazi, Gregory Wiseman, Lale Kostakoglu, Klemens Scheidhauer,Andreas Buck,

Ralph Naumann, Karoline Spaepen, Rodney Hicks, Wolfanf Weber, Sven Reske,

Markus Schywaiger, Lawrence Schwartz, Josee Zijlstra, Barry Siegel and Bruce Cheson

J. Clin. Oncol. 25:571-578, 2007

Response evaluation in lung cancer:RT and CT/RT

OS by CT response

MacManus, JCO 2003

OS by PET response

Evaluation of response to ChT in NSCLC

TTP:163 vs 54 days

p=.0003OS:252 vs 151 days

p=.005

Weber et al, JCO 2003

Mesothelioma

• Mesothelioma diffusely encases pleural cavity

• Mesothelioma causes morbidity and mortality through local disease rather than metastatic tumor burden

• Chemotherapy in mesothelioma is palliative – however responding patients demonstrate improved symptoms, improved QOL and increased survival

Response assessment

• CT response assessment is challenging due to the rind-like pattern of tumor growth.

• Modified RECIST criteria (Byrne and Nowak, Annals Oncol 2004;15:257-260) -measurements perpendicular to pleural surface

- 2 positions at 3 separate levels- measurements on f/up scans at same position and same level

• Limitations – time consuming, subject to error, relatively insensitive, no account of ‘viability’ of tissue, often require 3-4 cycles of chemotherapy to attain ‘PR’

• Mesothelioma is FDG-avid• Studies showing emerging utility in staging and

prognosis

Mesothelioma – CT measurements

Baseline Post chemotherapy

• Patients with histologically proven MPM not candidates to curative surgery

• Evaluated with FDG at baseline and after 2 courses of chemotherapy

• CT scans at baseline and after every two cycles of chemotherapy

• CT response compared to PET metabolic response• PET metabolic response = 25% SUVmax(bw) change

Early response in mesotheliomaA patient classified as SD on CT and as PR on PET

SUVmax 5.09SUVmax 2.78

Sarcomatoid mesotelioma

Sarcomatoid mesotelioma

Sarcomatoid mesotelioma

Stage IV sarcomatoid mesotelioma

SUV max 7.7

Stage IV sarcomatoid mesotelioma

Early response in mesotheliomaKaplan-Meier curve of time to disease progression by PET and CT

0

25

50

75

100

0 6 12 18 24

time to progression (months)

pro

po

rtio

n p

rog

ress

ed (%

)

0

25

50

75

100

0 6 12 18 24

time to progression (months)p

rop

ort

ion

pro

gre

ssed

(%)

PET response: p=0.02 CT response: p=0.57

PET scan - coronal slices

PET scan - region growing algorithm

Francis et al., JNM 2007

Survival

0.0970.65 (0.12-1.05)SUVmax 10% change

0.0150.64 (0.26-0.94)TGV 10% change

1.1310.71 (0.21-1.07)CT 10% change

p valueHazard ratioAfter 1 cycle chemotherapy

Francis et al., JNM 2007

FDG PRE

MET PRE

MET POST

Conclusions

• There is evidence that FDG PET can be used to assess tumorresponse to chemo- and chemoradiotherapy

• The technique is of value for malignant lymphomas and for manysolid tumors

• Visual interpretation of PET scans is sometime sufficient forassessment of tumor response after completion of therapy.

• Quantitative analysis of tumor uptake should be used in predictingtumor response early in the course of therapy

• In many cases SUVs seems to be adeguate to measure relative changes in tumor glucose use during therapy

• It is essential to follow a strict protocol for data acquisition, imagereconstruction, and data analysis in order to reliably measurechanges in tumor uptake with SUVs