1. Use of PET to Biologically Characterize Tumors and Monitor Their Response to Treatment Juan A del Regato Lecture Stanford 2004 Lester J Peters MD 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 – 18 F 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 Quarter PET/FDG Studies

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

6. Lab-based Predictive Assays Para- meter MethodPredictive value in reported studies Clinical Utility SF 2 In vitro cell survival most negativeNone T pot BUdR flow cytometry most negativeNone pO 2 Eppendorf probemost positiveNone NIn vitro plating efficiency too few to assessNone

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 pO 2 (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. The Allegretto Small-Animal (3D-GSO) PET scanner Prototype devices for U Penn and Peter Mac in June 2003 PET for Translational Research Small Animal Imaging

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

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

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

13. Small Animal PET Validation 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 20 24 27 Day

14. Human Studies with Novel Tracers at Peter Mac

15. Comparison of Metabolism and Proliferation F-18 FDGF-18 FLT 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

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

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

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

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

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. TROG 98.02 Arm 1 – Radiotherapy 70 Gy/ 7 wks with “Chemo-boost” cisplat +5FU Arm 2 – Radiotherapy 70 Gy/ 7 wksArm 2 – Radiotherapy 70 Gy/ 7 wks with cisplat +tirapazamine Stage III or IV H&N SCC 13 institutions Stratify by InstitutionRANDOMISE

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/m 2 T = Tirapazamine, 290 mg/m 2 with cis, 160 mg/m 2 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) cis/FUcis/TPZ Median age5558 Stage IV79%83% T4 and/or N345%47% ECOG 0,1,257,38,556,41,3

26. T4 SCC palate and oropharynx

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

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

30. Failure-free Survival

31. Overall Survival

32. Differences from Stanford Trial Pinto 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

33. Hypoxia Imaging – F MISO

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

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

36. 45 patients had baseline imaging of tumor hypoxia with F-MISO

37. Failure Pattern in F-MISO Scanned Patients L-R Failure by Treatment RT/Cis/FURT/Cis/TPZ Non-hypoxic1/10(2/3) Hypoxic8/131/19 Rischin et al, unpublished data, 2003

38. Time to Locoregional Failure by Treatment and Hypoxic Status

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

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

41. Close-up neck

42. Aug 97 midway thru TPZ/RT

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

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

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

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

47. 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

48. 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) +/- 18 F 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

49. Conventional Assessment vs PET in 44 Evaluable Patients 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%)

50. 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%)

51. Survival by PET findings

52. Utility of PET to Obviate Planned Neck Dissection Standard practice to dissect necks of patients with primary CR, but residual palpable abnormality in the neck 6-8 wks after radical chemoRT Neck dissection is inappropriate if unnecessary (no viable residual) or futile (disease outside neck)

53. Neck node study – Eligibility Node + ve Stage III-IV mucosal HNSCC treated definitively CR at primary site with residual palpable or CT/MRI neck mass ≥8 weeks after completion of treatment assessed by PET Pathologic confirmation or sufficient FU (>12 mths) to verify true neck status Porceddu et al, Head and Neck in press, 2004

54. Patient population 39 patients median age 55 (37-89) –Male 29 –Female 10 Primary sites –Oropharynx 31 –Larynx 5 –Hypopharynx 3

55. PET scans Performed to guide neck management at median 12 (8-32) wks post treatment Objective of PET to detect residual viable tumor in neck and/or presence of distant disease Accuracy assessed by pathology or clinical evolution with median FU 39 mths (15-88 mths)

56. T and N staging T stage N stage1234Total 101001 2a15309 2b23128 2c037111 3360110 Total61811439

57. Treatment Chemo-radiotherapy 34 –Chemoboost 22 –TPZ/cisplat regimen 12 Radiotherapy alone –Standard fractionation 1 –Altered fractionation 4

58. Results (n=39) Initial neck stage: N1: 1 N2: 28 N3: 10 Residual nodal size: 1.5 cm (0.8-3.5cm) PET negative in 32 patients 27 observed 1 neck failure (P+N) 5 neck dissections All path negative PET positive in 7 patients 7 neck dissections 5 path positive

59. Results (cont) Survival: 26 of 39 pts alive NED Pattern of failure –2 loco-regional relapse (P+N) –7 distant metastases –2 metachronous lung primary –2 unrelated causes –0 isolated neck relapse

60. Predictive value of PET 32 patients PET – ve in neck 5 had neck dissection, all path – ve 27 observed with 1 failure (in primary site and neck) 31 true negative, 1 false negative Negative predictive value 97%

61. Explanatory hypothesis Repopulation occurs rapidly in H&N cancer (median time to clinical recurrence 6 mths) Clonal regeneration leads to nodular, rather than diffuse recurrence By 12 weeks, resolution of PET is sufficient to detect most recurrences

62. Time frame important Scanning too soon after RT is less accurate –Rogers et al (IJROBP 2004) reported 5 of 6 false negatives in patients scanned 4 weeks post treatment –Kubota et al (EJNMMI 2004) reported 91% negative predictive value in 43 lesions in 36 patients scanned 4 months post treatment –False positives also more likely soon after radiotherapy because of residual inflammatory reaction

63. Outcomes in Peter Mac series

64. Current Peter Mac protocol 8 weeks Clinical Exam 12 weeks Clinical Exam & CT/MRI PET Scan Observe# Neck Dissection Observe* Selective Neck Dissection Primary CR Neck NR or PD Neck CR PET + PET - Primary CR Neck PR Node >1cm stable for ≥2 mths *Regular FU schedule #Monthly until CR achieved

65. Therapeutic Monitoring Does Metabolic Response Predict Survival in NSCLC?

66. Aims of Study 1) To study correlation between 18 F FDG PET response and survival in NSCLC following radical (chemo) RT 2) To determine if PET can delineate a sub-group of patients who may benefit from additional therapy Mac Manus et al, JCO 21:1285, 2003

67. Metabolic Response Assessment Fused pre- and post-treatment PET scans displayed using SUV calibrated scale Uptake in irradiated lung beyond initial tumor volume assessed separately as measure of radiation pneumonitis

68. Metabolic Response Primary metabolic CR with associated radiation pneumonitis

69. Before chemo-RT 2 months post treatment Complete Response : (Tumoral uptake=Mediastinal)

70. Partial Response Persistent disease 14 weeks post RT CR post salvage surgery: Path confirmed viable tumor Baseline study

71. PET Responses in 88 Patients Scans performed median 70 days post RT CR 40 (45%) PR32 (36%) NR 5 (6%) PD11 (13%)

72. Survival by PET Response

73. Survival by PET Response Grouped for Lung Radiotoxicity Hicks et al, IJROBP, in press, 2003 no

74. Conclusions – PET Response PET-response to radical RT/chemo RT separated patients into groups with widely differing survival probabilities Response less than CR associated with poor survival PET may identify patients suitable for salvage therapy

75. Overall Conclusions FDG PET has established itself as having an invaluable role in radiation oncology New tracers permitting biological characterisation of tumors are becoming available Access to PET/CT imaging should be an integral part of modern radiation oncology practice

76. Acknowledgements Special thanks to colleagues at Peter Mac: Rod Hicks, PET Centre Director Rob Ware, PET Centre Sandro Porceddu, H&N Unit Michael Mac Manus, Lung Unit for their help in preparing this lecture