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RESPONSE PREDICTORS TO TARGETED THERAPIES

RESPONSE PREDICTORS TO TARGETED THERAPIES. Stefano Fanti. DIAGNOSTICS. THERAPY. PET AND THERAPY. Accurate staging . Correct therapeutic choice. Correct prognosis definition (DFS, OS). More therapy?. End treatment. Prognosis (DSF, OS). Th response. Change in therapy?. Interim PET.

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RESPONSE PREDICTORS TO TARGETED THERAPIES

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  1. RESPONSE PREDICTORS TO TARGETED THERAPIES Stefano Fanti

  2. DIAGNOSTICS THERAPY

  3. PET AND THERAPY • Accurate staging Correct therapeutic choice 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

  4. 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 > 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

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

  6. 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.

  7. 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

  8. 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

  9. HD FDG PET and CT

  10. 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 PETFN ? PR PET FP?

  11. 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.

  12. HD PATIENT STUDIED BEFORE AND AFTER 2 CYCLES OF CHT: COMPLETE RESPONSE STAGING BEFORE CHT AFTER 2 CYCLES OF ABVD

  13. End Therapy PET has high VPP e VPN correlates with OS Spaepen, BJ Haemat.2001

  14. June 2004. FDG PET Staging. MIP 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)

  15. HD • After del II cycle  early evaluation • PET: residual disease. June 2004 Ago 2004

  16. HD • After VI cycle CT • CT: reduction of 75% of lymph nodes involvemet (RECIST:CR) • PET: PD (increased uptake). Ago 2004 Dec 2004

  17. HD High doses CT Sept 2005: RT on residual disease PET  PD Dec 2005 Dec 2004

  18. After 1 cycle: high PPV and NPV Kostakoglu L. et al.

  19. PET: Early response assessment Lymphoma Solid tumors • Rectal • Lung • Oesophageal • Breast • Head and neck • Pancreas • Ovarian • Soft tissue • Sarcomas • Cervix • Gastric • GIST

  20. AM • staging • Plurifocal breast lesions • N+ M+ (sternum) • Pathologic remission 90% (SUVmax 11.2) (SUVmax < 2)

  21. MS • operata il 18.1.2005 • remissione < 30% • grado 2

  22. SUV 4.1 31-12-2004 SUV 7.0 14-1-2005 • MS • operata il 18.1.2005 • remissione < 30% • grado 2 • 3/39 linfonodi positivi (con risposta grado C sui linfonodi)

  23. 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

  24. ResultsTiming

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

  26. SUVmax > 20 SUVmax 8.7 SUVmax 6.7 SUVmax< 2.0 11-04 12-04 2-05 2-05

  27. 31.3.2005 Staging SUV > 20 21.4.2005 SUV < 3.0

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

  29. PET: response assessment to targeted therapies Solid tumors • Rectal • Lung • Breast • Head and neck • Pancreas • Renal • Gastric • GIST

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

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

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

  33. 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

  34. PET: Early response assessment non FDG Solid tumors • Rectal • Lung • Oesophageal • Breast • Head and neck • Pancreas • Ovarian • Soft tissue • Sarcomas • Prostate • Gastric • GIST

  35. FDG PRE FDG POST SUVmax 5.5 SUVmax 4.5 SARCOMA: Before and after radiotherapy RESPONSE ?

  36. MET PRE MET POST SUVmax 16.9 SUVmax 4.2

  37. 90Y-DOTA-TATE

  38. 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

  39. SMALL ANIMAL PET • Receptorial ligands: • Integrins • Annexins • EGF • Somatostatin • Cannabinoid SR141716 • Adenosine: C11- KF21213: ligand CNS adenosine A(2A) receptors • Dopamine: F-DOPA • Androgens • Estrogens • Metabolic tracers: • 18F-FDG • 11C-Choline • 11C-Methionine • 18F-DOPA • 18F-FLT • 18F • 11C-Acetate • 124I • Tracers for hypoxia (…nitroreductase): • 18F-MISO • 18F-FETA • 18F-FAZA • Spatial Resolution • Depth • Temporal Resolution • Sensitivity • Molecular Probe detection (ng) • Reporter probes 18F-FHBG….

  40. IN VIVO MONITORING TUMOR DEVELOPING (MODELLING)

  41. P=0.018 No.10 No. 7 d 2 d 20 • RMS xenograft murine model treated with anti-MYCN PNA

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