ALMA MATER STUDIORUMUNIVERSITÀ DI BOLOGNA

Azienda Ospedaliero-Universitaria di BolognaPoliclinico S.Orsola-Malpighi

RESPONSE

PREDICTORS TO

TARGETED THERAPIES

Stefano Fanti

DIAGNOSTICS

THERAPY

PET AND THERAPY

Accurate staging Correct therapeutic choice

Correct prognosis definition (DFS, OS)

End treatment

Interim PET

More therapy?

Prognosis (DSF, OS)

Change in therapy?

Accurate staging

Definition of target volume

Response to therapy

Th response

RT planning

• CR: disappearence of all target lesions confirmed at > 4 weeks

• PR: > 30% decrease from baseline confirmed at > 4 weeks

• PD: > 20% increase from baseline or appearance of new lesions

• SD: neither PR or PD

RECIST Critera for the evaluation of response to treatment in solid tumors with Conventional Imaging :

RECIST CRITERIA

An appropriate evaluation is possible only after 4 weeks; an early

evaluation is often difficult or not possible

Anatomical post therapy changes (fibrosis etc ) can lead to over

estimate the presence of disease. On the other hand a consistent

reduction in size, do not exclude the persistence of disease, so it is

possible to under estimate the presence of residual disease.

New anti-angiogenetic agents are cytostatic and not necessarily

cytotoxic: a reduction in the size of tumor is not to be expected when

these agents are employed.

Interobserver variability

Limitation of RECIST and WHO criteria in the evaluation of response to chemo and radiation therapy in solid tumors.

S. J. Gwyther: Current standards for response evaluation by imaging techniques EJNM 6/2006

In oncology mass dimension may mean nothing.

Mass dimensions change over a long time after therapy.

Especially after therapy, a big mass can be fibrotic, a small mass can be active cancer.

MASS AND METABOLISM: FUNCTIONAL RESPONSE TO THERAPY

EORTC CRITERIA

• CR: same metabolic rate as normal tissue

• PR: after I cycle 15-25% decrease in SUV after II cycle > 25% decrease in SUV

• PD: > 25% increase of SUV or apparence of new lesions

• SD: difference of –15% to +25% in SUV; same extension

SUV

Main advantages of SUV in the measurements of glucose metabolism

• Requires only a single scan 60 minutes after i.v. injection of FDG• No blood sampling• Fast and easy to calculate

HD

FDG PET and CT

CRPET TN

PRPET TP

PRPET FN ?

Potential pitfalls (FP or FN) of FDG PET in the evaluation of response to therapy in solid tumors or lymphoma.

PRPET FP?

Limitation of metabolic response assessment criteria in the evaluation of response to chemo and radiation therapy in solid tumors.

end points:

• evaluate the efficacy of the current treatment.

• switch to more aggressive therapies in case of NON response

• reduce toxicity in case of early metabolic CR

• correlate with DFS and OS.

END TREATMENT EVALUATION

EARLY RESPONSE ASSESSMENT

HD PATIENT STUDIED BEFORE AND AFTER 2 CYCLES OF CHT: COMPLETE RESPONSE

STAGING BEFORE CHT

AFTER 2 CYCLESOF ABVD

Spaepen, BJ Haemat.2001

End Therapy PET has high VPP e VPN correlates with OS

HD

•F, 32 yo•May 2004: Biopsy HD, classical•June 2004: FDG PET staging IIIB, Bulky mediastinum CT total body: same as PET 28/06/2004: CT (6 cycles ABVD)

June 2004. FDG PET Staging. MIP

HD

After del II cycle early evaluation•PET: residual disease.

Ago 2004June 2004

HD

After VI cycle CT•CT: reduction of 75% of lymph nodes involvemet (RECIST:CR)•PET: PD (increased uptake).

Dec 2004Ago 2004

HD

High doses CTSept 2005: RT on residual disease PET PD

Dec 2004 Dec 2005

Kostakoglu L. et al.

After 1 cycle: high PPV and NPV

•Rectal •Lung •Oesophageal•Breast•Head and neck•Pancreas•Ovarian•Soft tissue •Sarcomas •Cervix•Gastric•GIST

Solid tumors

PET: Early response assessment

Lymphoma

(SUVmax 11.2) (SUVmax < 2)

AMstaging•Plurifocal breast lesions•N+ M+ (sternum)

•Pathologic remission 90%

SUV 9.5 (staging) 8-04

SUV 5.4 2-12.04 SUV 4.1 31-12-2004

MS•operata il 18.1.2005

• remissione < 30% grado 2

MS•operata il 18.1.2005

•remissione < 30%

grado 2

•3/39 linfonodi positivi (con risposta grado C sui linfonodi)

SUV 4.1 31-12-2004 SUV 7.0 14-1-2005

•PV operata il 21.2.2005:

• remissione < 90% (grado 3)

• 31/32 linfonodi positivi (risposta sui linfonodi grado C): PET falsa negativa fare linf. Sentinella!

11-04 staging SUVmax 8.0 12-04 SUVmax 5.1 3-2-05 SUVmax < 2.0

ResultsTiming

Average % Reduction of SUV (Ovary)

48%

60%

73%79% 80% 80%

35%

54%62%

70% 72% 70%

28%

39%

26%

43%49% 49%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

After 1st After 2nd After 3rd After 4th After 5th After 6th

Cycles of CHT

Av

era

ge

% S

UV

Red

uct

ion

Responders All patients NON responders

J Clin Oncol. 2006 Dec 1;24(34):5366-72.

BREAST CANCER

11-04 12-04 2-05 2-05

SUVmax< 2.0SUVmax 6.7SUVmax 8.7SUVmax > 20

31.3.2005 Staging SUV > 20 21.4.2005 SUV < 3.0

OVARIAN CANCER

J Clin Oncol. 2005 Oct 20;23(30):7445-53

•Rectal •Lung •Breast•Head and neck•Pancreas•Renal•Gastric•GIST

Solid tumors

PET: response assessment to targeted therapies

GASTRIC CANCER: Folcetux before and after (40 days)COMPLETE RESPONSE

GASTRIC CANCER: Folcetux before and after (43 days)STABLE DISEASE

GASTRIC CANCER: Folcetux before and after (35 days)PARTIAL RESPONSE

18F-TYR

18F-FMT

18F-FET

18F-DOPA

18F-OCT

18F-TOCA

18F-FLT

18F-FBAU

18F-FMAU

18F-FAU

18F-FEC

18F-FBM

18F-FCH

18F-FPC

18F-MEC

18F-FES

18F-FMOX

18F-FESD

18F-FENP

18F-FMNP

18F-FDHT

18F-FMIB

18F-MEC

18F-MDH

18F-MISO

18F-FAZA

18F-FETN

18F-FETA

18F-EF1

18F-EF5

18F-NaF

18F-FU

18F-FAMP

18F-FHPG

18F-FHBG

18F-FIAU

18F-FPCV

18F-RGD

18F-TP

18F-FMAC

18F-FAMP

18F-SFB 18F-FBG

•Rectal •Lung •Oesophageal•Breast•Head and neck•Pancreas•Ovarian•Soft tissue •Sarcomas •Prostate•Gastric•GIST

Solid tumors

PET: Early response assessment non FDG

FDG PRE FDG POST

SUVmax 5.5 SUVmax 4.5

SARCOMA: Before and after radiotherapyRESPONSE ?

MET POSTMET PRE

SUVmax 16.9 SUVmax 4.2

90Y-DOTA-TATE

end points:

• predict the efficacy of the current treatment.

• switch to different therapies

• reduce cost and toxicity

END TREATMENT EVALUATION

EARLY RESPONSE ASSESSMENT

PREDICTION OF RESPONSE

SMALL ANIMAL PET

1. Spatial Resolution

2. Depth

3. Temporal Resolution

4. Sensitivity

5. Molecular Probe detection (ng)

Metabolic tracers:• 18F-FDG• 11C-Choline• 11C-Methionine• 18F-DOPA• 18F-FLT• 18F• 11C-Acetate• 124I

Receptorial ligands:• Integrins• Annexins• EGF• Somatostatin• Cannabinoid SR141716 • Adenosine: C11- KF21213: ligand

CNS adenosine A(2A) receptors• Dopamine: F-DOPA • Androgens• Estrogens

Reporter probes 18F-FHBG….

Tracers for hypoxia (…nitroreductase):• 18F-MISO• 18F-FETA• 18F-FAZA

IN VIVO MONITORING TUMOR DEVELOPING (MODELLING)

RMS xenograft murine model treated with anti-MYCN PNA

TBR SCAN BY SCAN PNA TREATED VS UNTREATED

0,00

0,50

1,00

1,50

2,00

2,50

3,00

SCANS

TB

R CONTROLSCASES

CONTROLS 1,73 1,69 1,96 2,42

CASES 1,67 1,11 1,13 1,17

1 2 3 4

d 2 d 20

P=0.018

No.10No. 7

RMS XENOGRAFT MURINE MODEL TREATED WITH A NEW MOLECULE

UNTREATED

UNTREATED

TREATEDTREATED

NEW RADIOPHARMACEUTICALS

1. Commonly used compounds are sensitive but not specific for the disease under evaluation (18F-FDG, 11C-Choline, 11C-Methionine….).

2. They highlight hypermetabolic processes (tumors, inflammation, granoulomatous diseases….) over a background.

3. Aim: to develop radiopharmaceuticals specific for the disease under evaluation, for a specific metabolic feature or labeling a therapeutic molecule to assess its distribution inside the tumor.

NEW RADIOPHARMACEUTICALS

To develop radiopharmaceuticals specific for the therapeutic mechanism under evaluation, for a specific receptor or another feature of the drug in order to predict its efficacy.

68Ga-DOTA-NOC

Staging of NET, CI shows several liver lesions, PET identified primary tumour

EGFR: receptor involved in cancer growth. The tumor epitelium is dependent from EGFR as well.

Radiolabeled EGFR ligand can be useful to detect tumor site and to predict response to a specific therapy.

EGF: reversible or irreversible

ligand.

NEW RADIO-PHARMACEUTICALS

U87 tumour (EGFR pos), 124I-X uptake 4h

+ =

U87 tumour (EGFR pos), 18F-X

UPTAKE 5 MIN

UPTAKE 60 MIN

UPTAKE 150 MINBIODISTRIBUTI

ON UPTAKE 60 MIN

PET AND THERAPY

End treatmentMore therapy ?

Prognosis

Therapy response

Interim PETChange therapy ?

Prognosis

Before treatmentTherapy ?

Prognosis

THANK YOU