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The Need for Quantitative Imaging in Oncology

This text discusses the need for quantitative imaging in oncology, its role in detection, staging, treatment planning, and assessing response. It highlights the differences between clinical practice and research, and the importance of measuring clinical benefit accurately. The text also explores the concepts of activity vs. benefit, survival endpoints, response rate criteria, and the predictiveness of response rate in determining treatment benefit. The BAY-43-9006 (sorafenib) study in RCC is used as an example to illustrate the design and measurement of tumor shrinkage.

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The Need for Quantitative Imaging in Oncology

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  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!

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

  13. CT helps in the removal of most structure noise

  14. Vast Amount of Data lung nodule case ctn048, ctn008 - section 17 From S. Armato

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

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

  17. 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

  18. 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

  19. 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?

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

  21. 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

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

  23. 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?

  24. BAY 43-9006 (sorafenib) Study Progression-Free Survival in RCC Patients Continuing Beyond Initial 12 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) 12 Weeks 24 Weeks * Responders at 12 week assessment with >25% tumor shrinkage

  25. 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

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

  27. 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

  28. Response Status Response Stable Disease Progressive Disease 80 70 PD at 6 wks PD at 18 wks 60 PD at 54 wks 50 Total Target Tumor Length (cm) 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 Time (weeks) TTP Better Categorizes Tumor Control Than Response Rate

  29. 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

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

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

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

  33. PTK/ZK: Changes in Ki Correlate With Changes in Size of Liver Metastases 60 50 40 30 P = .0001 20 10 Change in tumor size at day 52, % 0 40 0 20 80 100 120 140 160 60 – 10 – 20 – 30 – 40 Progressors – 50 Nonprogressors Mean Baseline MRI Ki, % Day 28

  34. 160 140 120 100 80 60 40 20 0 PTK/ZK: Ki Correlation With Clinical Outcome • Significant correlation between reduction in tumor blood flow and clinical outcome after treatment with PTK/ZK Progressors (n = 9) 1 60 P = .006 Nonprogressors (n = 12) 1 40 120 1 00 Mean Baseline MRI-Ki, % Mean Baseline MRI-Ki, % 8 0 60 4 0 2 0 0 Day 28 Day 2

  35. PTK/ZK: Optimal Dosing 160 Progressors 260 Day 28 240 Nonprogressors 140 220 200 120 180 100 160 140 AUC 0-24, hr•µM Mean Baseline MRI, % 80 120 100 60 80 40 60 40 20 20 0 0 0 0 800 200 400 600 20 40 60 80 180 100 120 140 160 200 1,000 1,200 1,400 1,600 1,800 2,000 2,200 AUC 0-24, hr•µM Dose, mg

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

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

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

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

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

  41. 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

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