RESPONSE PREDICTORS TO TARGETED THERAPIES

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RESPONSE PREDICTORS TO TARGETED THERAPIES

• Stefano Fanti

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DIAGNOSTICS
THERAPY
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PET AND THERAPY
Correct therapeutic choice

• Accurate staging

Correct prognosis definition (DFS, OS)
More therapy?
End treatment
Prognosis (DSF, OS)

• Th response

Change in therapy?
Interim PET
Accurate staging

• RT planning

Definition of target volume
Response to therapy
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RECIST CRITERIA
RECIST Critera for the evaluation of response to
treatment in solid tumors with Conventional
Imaging

• CR disappearence of all target lesions
  confirmed at gt 4 weeks
• PR gt 30 decrease from baseline confirmed at
  gt 4 weeks
• PD gt 20 increase from baseline or appearance
  of new lesions
• SD neither PR or PD

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

• 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

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MASS AND METABOLISM FUNCTIONAL RESPONSE TO
THERAPY

• 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.

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EORTC CRITERIA

• CR same metabolic rate as normal tissue
• PR after I cycle 15-25 decrease in SUV
• after II cycle gt 25 decrease in SUV
• PD gt 25 increase of SUV or apparence of new
  lesions
• SD difference of 15 to 25 in SUV same
  extension

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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

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HD
FDG PET and CT
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Limitation of metabolic response assessment
criteria in the evaluation of response to chemo
and radiation therapy in solid tumors.
Potential pitfalls (FP or FN) of FDG PET in the
evaluation of response to therapy in solid tumors
or lymphoma.
CR PET TN
PR PET TP
PR PET FN ?
PR PET FP?
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END TREATMENT EVALUATION
EARLY RESPONSE ASSESSMENT

• 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.

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HD PATIENT STUDIED BEFORE AND AFTER 2 CYCLES OF
CHT COMPLETE RESPONSE
STAGING BEFORE CHT
AFTER 2 CYCLES OF ABVD
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End Therapy PET has high VPP e VPN correlates
with OS
Spaepen, BJ Haemat.2001
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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)

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HD

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

Ago 2004
June 2004
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HD

• After VI cycle CT
• CT reduction of 75 of lymph nodes involvemet
  (RECISTCR)
• PET PD (increased uptake).

Dec 2004
Ago 2004
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HD
High doses CT Sept 2005 RT on residual disease
PET ? PD
Dec 2005
Dec 2004
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After 1 cycle high PPV and NPV
Kostakoglu L. et al.
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PET Early response assessment
Lymphoma
Solid tumors

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

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• AM
• staging
• Plurifocal breast lesions
• N M (sternum)
• Pathologic remission 90

(SUVmax 11.2)
(SUVmax lt 2)
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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 lt 30
• grado 2

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

• MS
• operata il 18.1.2005
• remissione lt 30
• grado 2
• 3/39 linfonodi positivi (con risposta grado C sui
  linfonodi)

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• PV operata il 21.2.2005
• remissione lt 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 lt 2.0
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ResultsTiming
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BREAST CANCER
J Clin Oncol. 2006 Dec 124(34)5366-72.
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SUVmaxlt 2.0
SUVmax 6.7
SUVmax 8.7
SUVmax gt 20
11-04 12-04 2-05 2-05
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31.3.2005 Staging SUV gt 20
21.4.2005 SUV lt 3.0
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OVARIAN CANCER
J Clin Oncol. 2005 Oct 2023(30)7445-53
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PET response assessment to targeted therapies
Solid tumors

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

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GASTRIC CANCER Folcetux before and after (40
days) COMPLETE RESPONSE
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GASTRIC CANCER Folcetux before and after (43
days) STABLE DISEASE
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GASTRIC CANCER Folcetux before and after (35
days) PARTIAL RESPONSE
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18F-TYR
18F-FMAU
18F-FMOX
18F-MISO
18F-FAMP
18F-FMT
18F-FAU
18F-FESD
18F-FAZA
18F-FHPG
18F-FET
18F-FEC
18F-FENP
18F-FETN
18F-FHBG
18F-DOPA
18F-FBM
18F-FMNP
18F-FETA
18F-FIAU
18F-OCT
18F-FCH
18F-FDHT
18F-EF1
18F-FPCV
18F-TOCA
18F-FPC
18F-FMIB
18F-EF5
18F-RGD
18F-FLT
18F-MEC
18F-MEC
18F-NaF
18F-TP
18F-FBAU
18F-FES
18F-MDH
18F-FU
18F-FMAC
18F-FAMP
18F-SFB
18F-FBG
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PET Early response assessment non FDG
Solid tumors

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

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FDG PRE
FDG POST
SUVmax 5.5
SUVmax 4.5
SARCOMA Before and after radiotherapy RESPONSE ?
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MET POST
MET PRE
SUVmax 16.9
SUVmax 4.2
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90Y-DOTA-TATE
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END TREATMENT EVALUATION
EARLY RESPONSE ASSESSMENT
PREDICTION OF RESPONSE

• end points
• predict the efficacy of the current treatment.
• switch to different therapies
• reduce cost and toxicity

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SMALL ANIMAL PET

• 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

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

1. Spatial Resolution
2. Depth
3. Temporal Resolution
4. Sensitivity
5. Molecular Probe detection (ng)

• Reporter probes
• 18F-FHBG.

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IN VIVO MONITORING TUMOR DEVELOPING (MODELLING)
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RMS xenograft murine model treated with
anti-MYCN PNA
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RMS XENOGRAFT MURINE MODEL TREATED WITH A NEW
MOLECULE
UNTREATED
TREATED
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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.

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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.

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68Ga-DOTA-NOC
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Staging of NET, CI shows several liver lesions,
PET identified primary tumour
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• NEW RADIO-PHARMACEUTICALS

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.
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U87 tumour (EGFR pos), 124I-X uptake 4h
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U87 tumour (EGFR pos), 18F-X
BIODISTRIBUTION UPTAKE 60 MIN
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PET AND THERAPY

• Therapy response

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THANK YOU