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Positron Emiss ion Tomogra phyfor Treatme nt Assessment

Robert JerajDepartment of Medical PhysicsUniversity of Wisconsin – Madison, WI

rjeraj@wisc.edu

ANATOMICAL

BEFORE THERAPY AFTER

|||| |||| |||| |||| |||| …... |||| ||||

RESPONSE EVALUATION

TUMOR RESP., EARLY TOX LOCAL FAILURE, LATE TOXICITY

days, weeks months, years

DIAGNOSIS

STAGING

TARGET DEF.

RT PLANNING

MOLECULAR

Role of imaging in onco logy

IGRT

Why treatment assessment?

� Based on early treatment assessment one could modifytreatment:– If likely not succ essful:

• Escalate therapy• Change therapy• Selectively add dose (RT)

– If likely success ful:• Deescalate therapy• Stop therapy early

� Enormous benefit s for the patient - improved tumorcontrol, reduced side effects, and costs

Treatment asses smen t now

� Hist opatholo gic al evaluation:– Typically by regression score (viable tumor vs. fibrosis),

e.g., Salzer-Kuntschik for osteosarcomas– Limitations: need complete resection, problem with point

biopsies because of tumor heterogeneities

� Radiolog ical evaluation:– Defined by the therapy-induced reduction of tumor size:

WHO, RECIST– Limitations: numerous

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Anatomic resp onse criteria

� WHO (Miller, Cancer, 207, 1981):– the size of a tumor should be estimated based on two

perpendicular diameters– positive tumor response to therapy should be defined as

a reduction of at least 50% in the product of these twodiameters

� RECIST (Respon se Evaluation In Sol id Tumors)(Therasse , JNCI, 205, 2000):– The size of a tumor is estimated based on

unidimen sional measureme nt– Positive tumor response to therapy is at least 30%

decrease in the largest dimension of the tumor

� Comple te Response (CR): Disappearance of all disease comparedwith the baseline examination, whether it be measurable or not

� Partial Response (PR): A reduction in the sum of the greatest lengthsof individual tumors by at least 30% compared with the baselinemeasurement

� Progres sive Disease (PD): An increase in the total length of allmeasurable lesions of more than 20% compared with the smallest sumof lesion sizes (not the baseline values), or the appearance ofunequivocal new disease

� Stab le Disease (SD): This lies between the definitions for PR and PD

RECIST

Ideal…

Jaffe, J Clin Oncol, 24, 3245 (2006)

… and reality

Inherent inconsistencies in expert observers: 15-40%

Jaffe, J Clin Oncol, 24, 3245 (2006)

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Other issues …

� Tumor shri nkage is only the final step in a complexcascade of cellular and subcellular changes after treatment

� Several cycles of therapy (radiotherapy fractions,chemotherapy) are needed before treatment response canbe assessed by anatomic imaging

� Residual mass is often present after treatment – it is hardto differentiate between viable tumor posttreatmentchanges, such as scarring and fibrosis.

Visual example

Gwyther, Eur J Nucl Med Mol Imaging, 33, S11 (2006)

CT scan and comparable FDG-PET scan in a patient with gastro intestinalstromal tumor (GIST) with hepatic metastatic lesions

Pre-trea tment 3 months post treatm ent

FDG PET respons e criteria

� EORTC FDG PET response criteri a(Young et al, Eur J Cancer 35(13), 1773, 1999):– Patient prepara tion – overnight (6h) fasting)– Timing of scans – within 2 weeks of Tx– Attenuation corrections – no recommendation– Uptake measur ements – SUVBSA recommended– Tumor sampli ng – SUVmax and SUVmean

– Respons e – complicated

Typical behavior of FDG upt ake

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� Complete Metabolic Response (CMR): Completeresolution of FDG uptake within the tumor volume

� Parti al Metabolic Respons e (PR): A reduction of aminimum of 15-25% in tumor FDG SUV after one cycle ofchemotherapy, and greater than 25% after more than onetreatment cycle. No recommendati on for radioth erapy!

� Progressive Metabolic Disease (PMD): Increase in FDGtumor SUV of greater than 25% within the tumor region, orincrease of extend of FDG uptake (20% in the longestdirection) or appearance of new lesions

� Stable Metabolic Disease (SMD): Increase of less than25% or a decrease of less than 15% in tumor FDG SUV andno visible increase in extent (20% in the longest dimension)

EORTC resp onse criteria Prognostic relevance of FDG-PETAFTER ther apy

3-30(>30,>60)>200Several 2001-04Lymphoma

<0.001<20>45152Grigsby 2004Cervix

<0.001195647Hellwig 2004

0.001<12>3673MacManus 2003Lung

0.0114>2470Swisher 2004

0.0057>3436Flamen 2002Esophagus

0.00218>6035Kunkel 2003Head neck

PSurvivalnon-resp (mo)

Surviva lrespond (mo)

Nopat

RefTumor

All chemoradiotherapy except lymphoma (chemo only)

Post-treatment metabolic response is highly predictive of overall survival

Prognostic relevance of FDG-PETDURING therapy

Vis

35%

20%

30%

35%

50%

Cri t

<0.0015>2430Kostakoglu 2002Lymphoma

<0.00117>4835Ott 2003Stomach

0.0055957Weber 2003Lung

0.0118>3820Wieder 2004

0.0420>4837Weber 2001Esophagus

0.00440>12047Brun 2002Head neck

PSurviva lnon-resp (mo)

Survivalrespo nd (mo)

Nopat

RefTumor

Mid-treatment metabolic response is highly predictive of overall survival

All chemotherapy 0 10 20 30 40 50 60 700

2

4

6

8

10

12

14

16

SU

Vm

ax

Time [days]

Average

FDG-PET and radiati on therapy

Baardwijk, Radiother Oncol, 82, 145 (2007)

RT

5

FDG-PET and radiation therapy

0 10 20 30 40 50 60 700

2

4

6

8

10

12

14

16

SU

Vm

ax

Time [days]

Average

Metabolic non-resp onders

Metabolic responders

RT

Baardwijk, Radiother Oncol, 82, 145 (2007)

Molecular imaging targe ts in oncology

Increas ed cellular metabolis mIncreased cellu lar metabolism ::--IncreasedIncreased glycolysisglycolysis--Increased aminoIncreased amino--acidacidmetabolismmetabolism

Subverted cellular regu lationSubverted cellula r regulatio n ::--Intracellular signalingIntracellular signaling--CellCell--toto--cell signalingcell signaling--ExtracellularExtracellular matrixmatrixsignalingsignaling

Rapid cellul ar prolife rationRapid cellul ar proliferation

Evading cellular deathEvading cellular death

Altere d tumor microe nvironme nt:-Hypoxia-Changes in perfusion-Changes in diffusion

FLT

FDG

CuATSM

FRGD

FAnnex in V

Pre-treat ment

Post -treatme nt

2.5

0

T/M

280 mm3

330 mm3

T/M=2.7

T/M=1.1

FLT-PET/CT

Respon se to targeted therapy in SCCAvast in (bevaci zumab ) thera py

Pre-treatmen t … 1 week laterFLT-PET/CT

15

0

SUV

Reiser et al, Clin Cancer Res, 14(9), 2824, (2008)

Response to chemotherapy in NHLGuani ne nucleotid e analogue prodru g (GS-9219)

6

post-therapy day 5 day 3 day 1

Responders

post-therapy day 1

11.4 ± 0.8

0.415.10.88Part ial -

respond er

0.71 ± 0.041.60 ± 0.14Non-

respon ders

0.30 ± 0.013.4 ± 0.20.79 ± 0.04Respo nders

Coeffic ientof Variation

MaxSUV

MeanSUV

Respon se to chemotherapy in AMLAntracycl ine, cytarabine and/or etop oside

Part ial–responder

Non-respon ders

10

0

SUV

FLT-PET/CT

Response to molecul ar targ eted therapySuniti nib melat e (Sutent )

5

0

SUV

FLT-PET/CT

Pre-treatment Week 4 Week 6

Sunitini b treatment withdrawal

No

n-r

esp

on

der

Res

po

nde

r

4

0

SUV

k1 (perfusion) VB (vasculatur e)

0.6

0

VB

0.3

0

k1

k1 (perfusion) VB (vascu latu re)

0.6

0

VB0.3

0

k1

Po

st-t

her

apy

Pre

-th

erap

y

Respon se to mol ecular targeted therapySunit inib melate (Sutent )

CuATSM -PET/CT CuATSM -PET/CT CuATSM -PET/CT

FDG-PET/CT FLT-PET/CT FLT-PET/CT

Pre-Avastin :Week 1

Pre-Avast in:W eek 1

Pre-RT: Week 3

Pre-RT: Week 3

Mid-RT: Week 5

Mid-RT: Week 5

7

0

SUV

20

0

SUV4

0

SUV4

0

SUV

7

0

SUV7

0

SUV

Response to combina tion therapyBevac izumab + Bevac izuma b/Cisplatin/RT

7

Pre

-tre

atm

ent

Mid

-tre

atm

ent

(1w

kof

XR

T)

Response to radiation ther apyAdaptative radiotherapy

Pre

-tre

atm

ent

Mid

-tre

atm

ent

(1w

kof

XR

T)

Response to radiatio n ther apyAdaptative radio thera py

Respon se to radiation therapyTemporal development

Pre Day 3 Day 6

FLT-PET/CT

Response to radi ation therap yDose painting

Pre-treatment Mid-treatment Treatment respo nse

Dose painting plan Dose prescr iption Prescripti on functi on

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Post -RTPre-RT

Response to radiation ther apyNormal tissue response

Post -RTPre-RT

Response to radiatio n ther apyNorm al tissue respons e

Conclusion s

� Treatment assess ment has enormous potential tochange patient care

� Anatomical imaging used for treatmentassessment has many limitations

� Functional/mol ecular imaging is more powerfuland versatile in assessment of treatment response

� Respo nse crit eria are more complex, tumor andtracer dependent

� Need for clini cal trials with extensivefunctional/molecular imaging component

Thanks to:

� Image-guided therapy gr oup– Vikram Adhikarla– Dave Barbee– Steve Bowen– Joseph Grudzinski– Michael Daveau– Matt LaFontaine– Keisha McCall– Matt Nyflott– Peter Scully– Urban Simoncic– Chihwa Song– Benny Titz– Matt Vanderhoek– Stephen Yip

� Medic al Physic s– Jerry Nickles– Onofre DeJesus– Dhanabalan Murali– Rock Mackie– Sean Fain

� Radiology– Scott Perlman– Jamey Weichert– Chris Jaskowiak– Mark McNall

� Human Oncolog y– Søren Bentzen– Paul Harari– Mark Ritter– Minesh Mehta– Wolfgang Tome– Wendy Walker

� Medicine/UWCCC– George Wilding– Glenn Liu– Phase I office

� Hematolog y– Mark Juckett– Nancy Turman

� Veterinar y School– Lisa Forrest– David Vail

� NIH, NSF, Susan Komen Foundatio n,UWCCC