1. PET in Sarcoma Imaging Treatment Response CTOS 2004 Montreal J.F. Eary, M.D. University of Washington

2. Defining Tumor Response Conventional Imaging Conventional Imaging Tumor shrinkage, disappearance Tumor shrinkage, disappearance Tumor qualitative change Tumor qualitative change Clinical Exam Clinical Exam

3. Defining Tumor Response Clinical Questions 1. How early can response be detected? 2. Which is the best treatment agent? 3. Is an image response a surrogate for effectiveness of therapy? 4. Can patient outcome be inferred? 5. Does image response predict for patient outcome?

4. Tumor Response 1. Slowed growth 2. Stasis 3. Necrosis - coagulative, liquefactive 4. Hemorrhage 5. Serious fluid accumulations 6. Granulation tissue formation 7. Scar formation 8. Loss of vascularity 9. Loss of malignant elements

5. Re-Defining Tumor Response Quantitative tumor biological parameters 1. Metabolism 2. Receptor quantity 3. Proliferation 4. Uptake of thymidine agents

6. PET Contributions to Tumor Response Assessment 1. Quantitative 2. High spatial resolution 3. Biologically relevant imaging agents

7. Using PET to answer important questions in oncology– What are the critical differences between normal, malignant, and treated tissue? How can this information be used to understand the biochemical processes by which therapy kills or fails to kill cells? From all of the available options, what will be the best treatment for an individual patient?

8. PET Measurement as a Surrogate Endpoint for Patient Outcome Tumor staging and grading, including heterogeneity Following response to treatment Identifying the cause of resistance in the individual patient Prediction / detection of normal tissue damage Assessing metastases / metastatic potential

9. Factors in Response and Resistance Surface Receptors Octreotide Proliferative Rate Thymidine & Analogs Glycolytic Rate FDG Hypoxia FMISO, EF1, ATSM Efflux Pumps MIBI, Verapamil, Colchicine Nuclear Receptors FES, FDHT

10. 18 FDG is the most important PET procedure 2-fluoro-2-deoxy-D-glucose  FDG reflects altered tissue metabolism More than just “grading” images.

11. High Grade Sarcoma: Near Complete Response to Chemotherapy

12. ESFT: Response assessed by PET Before chemotherapy After chemotherapy

13. High Grade Sarcoma: Tumor Progression during Chemotherapy

14. Survival Based on Initial SUV 0.0 0.2 0.4 0.6 0.8 1.0 0204060 Time (months) Pre SUV<7 Pre SUV>7 Survival Probability

15. Survival Based on Post-Chemotherapy SUV

16. FDG PET in Chondrosarcoma

17. STS Survival Based on Change in Tumor SUV after Neoadjuvant Chemotherapy

18. STS Survival based on 40% change in SUV after Neoadjuvant ChemoRx

19. Can We Predict Response to Treatment? Quantitative FDG imaging Quantitative FDG imaging FMISO FMISO C-11 Thymidine C-11 Thymidine C-11 Verapamil C-11 Verapamil Quantitative FDG imaging Quantitative FDG imaging FMISO FMISO C-11 Thymidine C-11 Thymidine C-11 Verapamil C-11 Verapamil

20. High Grade Sarcoma: Heterogeneous Response to Chemotherapy

21. 3-D Ellipsoidal Model for Homogeneous Tumors Utilization U(x) as a function of position (x) is given by U(x) = g[ (x-m)’A(x-m) ] m is the relative location A is a shape matrix g is a monotone level function

22. Multivariate Survival Analysis Variable (Standardized) %Change in Risk 95% C.I. P-value SUV 32.2 32.2(13,54)0.0005 Heterogeneity(Elliptical) 36.2 36.2(11,68)0.0038 Heterogeneity (Boundary- Elliptical) 71.7 71.7(-54,542)0.42 N=179 (71 deaths) Volume, RD, Boundary Morphology, Age: All not significant

23. Liposarcoma PET Studies FDG Blood Volume Thymidine

24. PET Imaging of Factors that Limit Response to Therapy Hypoxia Hypoxia Direct effects: resistance to rads, chemo Direct effects: resistance to rads, chemo Indirect: genetic instability Indirect: genetic instability VEGF, mutant p53 VEGF, mutant p53 Multi Drug Resistance Multi Drug Resistance via P-glycoprotein via P-glycoprotein high energy requirement high energy requirement

25. PET IMAGING HIGH GRADE LEIOMYOSARCOMA 18 F-FMISO SUV MAX =3.2SUV MAX =13.6 FDG FMISO : identify treatment resistant tumors FMISO : identify response/re-oxygenation FMISO : select patients for Tirpazamine therapy

26. PET and Pharmacokinetics: [ 11 C]-verapamil as a marker for the transport of anti-HIV drugs Hypothesis: Blocking P-gp will increase the delivery of anti-HIV nucleosides to the brain (Sagittal images of a macaque) No inhibitor After Cyclosporine (P-pg inhibitor) Brain Uptake

27. [18F]-FBA-annexin V Images Rats were injected with 0.5 mCi and imaged for 10 min beginning at 60 min after injection. Apoptosis of liver was induced by injection of cycloheximide (5 mg/kg, 4 hr). Normal Apoptosis

28. Molecular Imaging Answers Early indicators of the effectiveness of therapy will improve care-- Reduce ineffective medication use Reduce ineffective medication use Reduce unhelpful procedures Reduce unhelpful procedures Reduce cost Reduce cost Improve survival and quality of life Improve survival and quality of life

29. DNA Microarrays DNA Microarrays