1. The Need for Quantitative Imaging in Oncology Richard L. Schilsky, M.D. Professor of Medicine, Associate Dean for Clinical Research, University of Chicago Chairman, Cancer and Leukemia Group B

2. The Role of Imaging in Oncology Detection Staging (assess prognosis) Treatment planning Assess response/progression (assess benefit) Monitor recurrence

3. The Role of Imaging in Oncology Is a tumor present? Where is it? How big is it? How deep is it? What is it near? Is it growing/shrinking/spreading?

4. Clinical Practice vs. Clinical Research Mostly a matter of precision Practice setting: information that impacts clinical management of an individual, e.g., when to start/change/stop treatment; assess extent of disease and cause of symptoms Research setting: information that assesses an intervention in a population, e.g., precise staging; accurate tumor dimensions; assessment of response/progression

5. Clinical Benefit Improved survival compared to no treatment or to a known effective therapy Non-inferiority to a known effective therapy Improvement in TTP compared to known effective treatment coupled with symptomatic improvement

6. Activity vs. Benefit Don’t confuse activity with benefit –Activity is the effect on a surrogate or clinical endpoint of administering the drug –Efficacy is the overall benefit (adjusted for risk) of prescribing the drug (for a specific indication) Activity is necessary – but not sufficient – for efficacy

7. Survival Unambiguous endpoint that is not subject to investigator interpretation or bias from unblinded studies Assessed easily, frequently No tumor measurements required!!

8. Response Rate Treatment is “entirely” responsible for tumor reduction; unlikely due to natural history Endpoint reached quickly Response criteria arbitrary %CR and duration of response important Classical endpoint to screen for activity; accepted surrogate for clinical benefit

9. Response Criteria WHO: PR is > 50% decrease in the sum of the product of the perpendicular diameters of measurable lesions RECIST: PR is > 30% decrease in the baseline sum of the longest diameters of target lesions Each represents a 65% decrease in volume Confirmation 4 weeks later required

10. Criteria for Progression WHO: PD is > 25% increase in the sum of the product of the perpendicular diameters of measurable lesions (40% increase in volume) RECIST: PD is > 20% in the sum of the longest diameters of target lesions (73% increase in volume) RECIST is biased toward stable disease

11. What is Measurable? Lesion measured in one dimension as > 20 mm with conventional techniques or > 10 mm with spiral CT (5 mm reconstruction) All measurable lesions up to max. of 10 are considered “target” lesions All of this is completely arbitrary and observer/technology-dependent!

19. You have to see it before you can measure it!

20. CT helps in the removal of most structure noise

21. case ctn0 48, ctn0 08 - secti on 17 lung nodule Vast Amount of Data From S. Armato

22. Erasmus, J. J. et al. J Clin Oncol; 21:2574-2582 2003 Measurable?

23. Erasmus, J. J. et al. J Clin Oncol; 21:2574-2582 2003 Measurable?

24. Is RR Predictive of Benefit? For hematologic malignancies, CR generally associated with symptomatic improvement, reduced transfusion requirement, reduced infection rates Buyse et. al. (Lancet, 2000): meta analysis of 25 CRC trials with fluoropyrimidines: tumor response a highly significant predictor of survival, independent of PS

25. Is RR Predictive of Benefit? Chen et. al. (JNCI, 2000): phase II response rates in patients with extensive SCLC did not correlate with median survival in phase III trials of same regimen Irinotecan (15%); docetaxel (38%); capecitabine (18.5%); oxaliplatin (9%) all improved survival in randomized trials In many other studies, a significant improvement in RR does not result in improved survival

26. Is RR Predictive of Benefit? RR is reasonably likely to predict clinical benefit, at least for certain diseases and certain drugs Is there a minimum RR predictive of benefit and how is it best measured? Is another surrogate predictive for drugs that do not cause regression?

27. BAY 43-9006: RDT Trial Schema > 25% Tumor shrinkage -25% to +25% Tumor stabilization > 25% Tumor growth BAY 43-9006 12 week run-in Continue BAY 43-9006 Continue BAY 43-9006 12 weeks Placebo* 12 weeks Off study % SD 24 weeks *Placebo pts with PD may cross over to BAY 43-9006

28. BAY 43-9006: RDT Design All patients initially receive BAY 43-9006 Enrichment of randomized population for endpoint of interest –Distinguishes antiproliferative activity of drug vs. the natural history of disease –Requires less overall sample size compared to RCT Design controls, in part, for heterogeneity in enrolled patients, as rapid progressors drop out

29. BAY 43-9006 (sorafenib) Study RCC Bidimensional Tumor Measurements* at Week 12: Change from Baseline in Target Lesions (n=89) % Change in Tumor Measurement Number of Patients > 25% Growth -25% Change >-25% to -49% Shrinkage > -50% Shrinkage 7 45** 24 13 * Investigator assessed * * 7 of 45 patients not randomized

30. Response vs. Stable Disease The distinction between “minor responses” and partial responses is based on arbitrary criteria The patient doesn’t care whether the tumor shrank by 40% (bidimensional) or 60% –So why should we?

31. BAY 43-9006 (sorafenib) Study Progression-Free Survival in RCC Patients Continuing Beyond Initial 12 Weeks * Responders at 12 week assessment with >25% tumor shrinkage 12 Weeks 24 Weeks Open Label BAY (n=37) Median = 48 weeks (88% progression free at 24 weeks) Randomized (n=38) Median = 23 weeks (41% progression free at 24 weeks)

32. Time to Progression Includes all patients in analysis Endpoint sooner than survival; no crossover effect Definition of progression -death due to cancer -new lesions -increase in size of existing lesions (?) -?increase in tumor metabolism -? increase in plasma level of tumor marker -? decline in PS or increase in symptoms

33. Tumor assessment frequency should be the same across study arms even when cycles are of different lengths Time to Progression Measurement Considerations Minimum interval between tumor assessments should be less than the expected treatment effect size

34. Time to Progression Precision depends on identification of all lesions at baseline and on frequency of evaluation Always an estimate since actual progression occurs between observations Requires control for rate of progression in absence of treatment effect Unblinded studies subject to ascertainment bias

35. Response PD at 18 wks TTP Better Categorizes Tumor Control Than Response Rate Progressive Disease PD at 6 wks 0 10 20 30 40 50 60 70 80 061218243036424854 Time (weeks) Total Target Tumor Length (cm) Response Status Stable Disease PD at 54 wks

36. How Things Are Changing Non invasive staging Imaging targets for dose finding Neoadjuvant chemotherapy to assess response Early response assessment Greater reliance on time to progression

37. Enzinger, P. C. et al. N Engl J Med 2003;349:2241-2252 PET-CT Staging of Esophageal Cancer

38. Lardinois, D. et al. N Engl J Med 2003;348:2500-2507 PET-CT Staging of NSCLC

39. DCE MRI in CRC Patient Treated with PTK 787 Ki dropped from 100% baseline to:31% on day 2 34% at end cycle 1 15% at end cycle 2 Baseline Day 2 Thomas et al. EORTC-NCI-AACR 2002.

40. PTK/ZK: Changes in Ki Correlate With Changes in Size of Liver Metastases Mean Baseline MRI Ki, % Day 28 20 40 60 80100120140160 60 50 40 30 20 10 0 – 10 – 20 – 30 – 40 – 50 Change in tumor size at day 52, % 0 Progressors Nonprogressors P =.0001

41. 0 20 40 60 80 100 120 140 160 P =.006 Significant correlation between reduction in tumor blood flow and clinical outcome after treatment with PTK/ZK PTK/ZK: Ki Correlation With Clinical Outcome 0 Progressors (n = 9) Nonprogressors (n = 12) 160 140 120 100 80 60 40 20 Mean Baseline MRI-Ki, % Day 2 Day 28 Mean Baseline MRI-Ki, %

42. PTK/ZK: Optimal Dosing Mean Baseline MRI, % 160 140 120 100 80 60 40 20 0 0 406080 100120140160 180 200 Progressors Nonprogressors AUC 0-24, hrµM 260 240 220 200 180 160 140 120 100 80 60 40 20 0 Dose, mg Day 28 0 200400600 800 1,0001,2001,4001,6001,8002,0002,200 AUC 0-24, hrµM

43. Quon, A. et al. J Clin Oncol; 23:1664-1673 2005 Estrogen receptor imaging using [18F]fluoroestradiol (FES) -PET scanning may predict breast cancer response to hormonal therapy

44. Early Response Assessment in GIST Dec 7, 2000Jan 1, 2001 After Gleevec™Before Gleevec™ Is quantitation necessary?

45. Weber, W. A. et al. J Clin Oncol; 21:2651-2657 2003 FDG PET to Assess Response

46. Weber, W. A. et al. J Clin Oncol; 21:2651-2657 2003 PET Association with Clinical Benefit

47. Sasaki, R. et al. J Clin Oncol; 23:1136-1143 2005 Overall survival according to the standardized uptake value (SUV) for the primary tumor

48. Conclusions Imaging is vitally important for staging and assessment of drug activity/tumor progression Quantitative imaging provides information that can be a surrogate for clinical benefit but refinements are needed in response criteria Functional imaging is increasingly useful for target assessment, dose-finding and early response assessment Oncologists and imagers must work as partners in cancer care and research