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Lester J Peters MD

Lester J Peters MD. Use of PET to Biologically Characterize Tumors and Monitor Their Response to Treatment Juan A del Regato Lecture Stanford 2004. Peter MacCallum Cancer Centre Melbourne, Australia. Outline – Role of PET in:. Biological characterization of tumors

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Lester J Peters MD

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  1. Lester J Peters MD Use of PET to Biologically Characterize Tumors and Monitor Their Response to TreatmentJuan A del Regato LectureStanford 2004 Peter MacCallum Cancer Centre Melbourne, Australia

  2. Outline – Role of PET in: • Biological characterization of tumors • Therapeutic monitoring and guidance of post-treatment intervention Illustrated by research at Peter MacCallum Cancer Centre in patients with advanced HNSCC and NSCLC

  3. History of PET facility at Peter MacCallum – Director Rodney J Hicks MD • 1996 Established with PENN-PET 300-H scanner –18F FDG purchased • 1998 Oxford cyclotron installed • 2001 GE Discovery PET/CT added All patients entered into prospective relational data base

  4. Quarterly PET/FDG studies Peter MacCallum Cancer Centre PET/FDG Studies Quarter

  5. Biological Characterization • Underlying concept for predictive assays • Objective to guide rational therapeutic interventions

  6. Lab-based Predictive Assays

  7. Problems with Lab-Based PAs • Invasive • Limited to accessible tumors • Heterogeneity vs sample size • Culture methods slow

  8. PET offers a New Approach to Biological Characterization • Specific tracers now available for measurement of pO2 (FMiso, FAZA, Cu ATSM),DNA (FLT) and protein (FET) synthesis rates • Volume of metabolically active tumor (FDG) may be a surrogate for clonogen cell number

  9. PET for Translational Research Small Animal Imaging The Allegretto Small-Animal (3D-GSO) PET scanner Prototype devices for U Penn and Peter Mac in June 2003

  10. Small Animal PETValidation Studies in Mice – F-18 Fluoride 18F fluoride PET bone scan of a mouse

  11. Small Animal PETValidation Studies in Mice – F-18 FLT F-18 fluorothymidine (FLT) for DNA synthesis • Transgenic mouse model with spontaneous lymphoma

  12. Small Animal PETValidation Studies in Mice - FET A431 xenograft in nude mouse F-18 fluroethyltyrosine (FET) for amino-acid transport

  13. Small Animal PETValidation Studies in Mice - FAZA F-18 FAZA PET scan in a 20gm nude mouse with A-431 xenograft Progressive growth of tumour associated with evidence of progressive central necrosis Day 20 24 27

  14. Human Studies with Novel Tracers at Peter Mac

  15. Comparison of Metabolism and Proliferation • 1.5cm solitary nodule in the right lower lobe • High risk biopsy due to poor lung function • No mediastinal nodes on CT • Assessment of suitability for “postage stamp” radiotherapy F-18 FDG F-18 FLT

  16. Comparison of Metabolism and Proliferation • Extensive right apical mass in young, non-smoker • Mediastinal lymphadenopathy but negative FNA and bronchoscopy • Subsequent positive serology for aspergillus F-18 FDG F-18 FLT

  17. Anti-Proliferative Response detected by FLT • Metastatic malignant melanoma involving spleen, small bowel and retroperitoneal nodes • Treated with anti-angiogenic compound (SU 11248) in Phase II trial p6098s1 p6098s2

  18. Tracers for PET Imaging of Hypoxia • 2-nitroimidazole compounds 18F-MISO 18F-EF5 18FAZA • non-nitro compound 60Cu ATSM

  19. Imaging for Hypoxia with FAZA FDG FAZA • T3 N1 SCC base of tongue • Central uptake in viable tumor and in left cervical node

  20. Comparison FAZA vs FMISO • T4N0 SCC post pharyngeal wall • Planned treatment with tirapazamine p5500s0s2 FAZA FMISO

  21. Hypoxia Imaging in Tirapazamine Trials Phase I PMCC patients only (n=16) all imaged with FMISO Phase II TROG 98.02 (n=122) 45 patients from PMCC imaged with FMISO Phase III HeadSTART (n=414/850) 65 patients from PMCC imaged with FAZA

  22. Arm 1 – Radiotherapy 70 Gy/ 7 wks • with “Chemo-boost” cisplat +5FU • Arm 2 – Radiotherapy 70 Gy/ 7 wks • with cisplat +tirapazamine TROG 98.02 Stage III or IV H&N SCC 13 institutions Stratify by Institution R A N D O M I S E

  23. Tirapazamine/Cisplatin/Radiation Regimen    week 1 week 2 week 3 week 4 week 5 week 6 week 7 70 Gy in 35 fractions, 5/week C+TC+TC+T T T C = Cisplatin 75 mg/m2 T = Tirapazamine, 290 mg/m2 with cis, 160 mg/m2 without cis

  24. Eligibility • Stage III or IV (excluding T1N1) SCC head and neck • No evidence of distant metastases • ECOG PS 0-2 • Calculated creatinine clearance > 55ml/min • No prior chemotherapy or radiotherapy for head and neck cancer

  25. Patient Characteristics(n=122)

  26. T4 SCC palate and oropharynx

  27. Outcome Patient clinically, radiologically and metabolically free of disease 2 years post treatment, with good salivary function

  28. Time to Loco-Regional Failure(n=122)

  29. Failure-free Survival

  30. Overall Survival

  31. Differences from Stanford TrialPinto et al, ASCO 2003 • Patient populations • Stanford patients all resectable • Early surgery for non-responders • Chemotherapy: TROG regimen • No induction therapy • More TPZ during RT • Front-end loading

  32. Hypoxia Imaging – F MISO

  33. Hypoxia Imaging FDG (Glucose) F MISO (Hypoxia) Carcinoma of larynx with hypoxic neck nodal mass p1597s0s1

  34. Therapeutic Outcome • Complete metabolic response in non-hypoxic primary but poor metabolic response in hypoxic lymph node • Persistent neck disease at surgery p1597s5 Post-treatment FDG

  35. 45 patients had baseline imaging of tumor hypoxia with F-MISO

  36. Failure Pattern in F-MISO Scanned Patients Rischin et al, unpublished data, 2003

  37. Time to Locoregional Failure by Treatment and Hypoxic Status

  38. Utility of PET in Patients with a Residual Structural Abnormality following Radical Treatment

  39. Jul 97 T3 N3 SCC L tonsil, post incisional Bx neck node

  40. Close-up neck

  41. Aug 97 midway thru TPZ/RT

  42. Dec 97 – residual induration, PET –ve; RND, path –ve

  43. Therapeutic Monitoring Baseline Evaluation 4 weeks into treatment • Left base tongue primary with bulky bilateral upper deep cervical lymphadenopathy • Clinical progression on treatment p710

  44. Sequential Scans Comparison of CT and PET response Early metabolic CR Partial, late CT response p710

  45. Sequential Clinical Response Long lag between metabolic and clinical response Complete local pathological response confirmed p710

  46. Post-treatment assessment • Rate of regression of tumor masses after treatment is highly variable • Residual metabolic activity in a treated cancer is much more significant than a residual mass

  47. Patients and Methods • 53 HNSCC patients with a residual structural abnormality following definitive therapy • Presence of active disease at index site or elsewhere assessed by conventional means (clinical + CT and/or MRI) +/- 18F FDG PET • Accuracy assessed by pathology or observation of disease evolution (min FU 41 mths for pts alive at close-out date) Ware et al, Head and Neck, in press, 2004

  48. Both Conv and PET PET only Conv only Neither Total accurate on PET Total accurate on Conv PET +ve predictive value PET -ve predictive value Number correct 16 23 2 3 39 18 95% (CI 77%-100%) 83% (CI 63%-95%) Conventional Assessment vs PET in 44 Evaluable Patients

  49. Impact of PET on Patient Management • PET resulted in change of management plan in 21 pts (40%), majority being avoidance of planned salvage surgery • Changed plan validated appropriate in 19/20 evaluable cases (95%)

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