Response Evaluation

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Response Evaluation

  1. 1. Response Evaluation: Beyond RECIST Elizabeth Eisenhauer MD FRCPC ESMO Conference Lugano 07 July 2007
  2. 2. Outline <ul><li>Background: </li></ul><ul><ul><li>Why measure response? </li></ul></ul><ul><ul><li>Response criteria in cancer trials </li></ul></ul><ul><li>Key aspects of RECIST </li></ul><ul><li>Implementation issues with RECIST </li></ul><ul><ul><li>Minimum number of lesions </li></ul></ul><ul><ul><li>RECIST in randomized trials </li></ul></ul><ul><ul><li>Imaging with MRI and PET </li></ul></ul><ul><ul><li>Is RECIST applicable in trials of non-cytotoxics? </li></ul></ul>
  3. 3. Why Measure Response? <ul><li>The word “response” is used in a number of contexts: </li></ul><ul><ul><li>To describe outcomes in daily practice (“my patient is responding to treatment”) </li></ul></ul><ul><ul><li>As a surrogate for benefit (e.g. in randomized trial) </li></ul></ul><ul><ul><li>As the primary endpoint in phase II “screening” trials where a decision is being taken about future of drug or regimen </li></ul></ul>
  4. 4. Why Measure Response? <ul><li>The word “response” is used in a number of contexts: </li></ul><ul><ul><li>To describe outcomes in daily practice (“my patient is responding to treatment”) </li></ul></ul><ul><ul><li>As a surrogate for benefit (e.g. in randomized trial) </li></ul></ul><ul><ul><li>As the primary endpoint in phase II “screening” trials where a decision is being taken about future of drug or regimen. RECIST criteria developed for this </li></ul></ul>
  5. 5. Response Criteria in Clinical Trials <ul><li>Clinical cancer research takes place in an international arena, thus we need a common, standard “language” to describe key methods and definitions for trial outcomes, such as </li></ul><ul><ul><li>Toxic effects: terms and grades </li></ul></ul><ul><ul><li>Time to event definitions </li></ul></ul><ul><ul><li>Tumour response definitions </li></ul></ul>
  6. 6. Response Criteria in Clinical Trials <ul><li>In early drug development: </li></ul><ul><ul><li>Tumour shrinkage has long been used to provide a “signal” that new agents may be effective </li></ul></ul><ul><ul><li>Anatomic-based criteria therefore required to describe and categorize patient outcomes </li></ul></ul><ul><ul><li>WHO/others defined CR, PR, SD, PD </li></ul></ul><ul><li>To be useful as endpoint, Response: </li></ul><ul><ul><li>Must be defined consistently </li></ul></ul><ul><ul><li>Must be implemented consistently </li></ul></ul>
  7. 7. Response Criteria in Clinical Trials <ul><li>Mid-late 1990s: International working group began to meet to address some shortcomings of WHO. For example: </li></ul><ul><ul><li>Complexity (bidimensional measurements) </li></ul></ul><ul><ul><li>New technologies (CT) </li></ul></ul><ul><ul><li>Silent on many areas so open to varying interpretation </li></ul></ul><ul><ul><li>i.e. the “standard” was no longer standard </li></ul></ul>
  8. 8. R esponse E valuation C riteria i n S olid T umors: “RECIST” Working Group <ul><li>1995: International representation from different research organizations </li></ul><ul><li>Revisit definitions, assumptions, implications </li></ul><ul><li>Harmonize to the best standards </li></ul><ul><li>Simplify where possible </li></ul><ul><li>Update with new concepts </li></ul><ul><li>An ongoing process……… </li></ul>EORTC: P. Therasse M. Van Glabbeke (S) A.T. van Oosterom J. Verweij NCI US: S. Arbuck L. Rubinstein (S) M. Christian R. Kaplan NCICCTG: E. Eisenhauer NDDO: J. Wanders UK: S. Gwyther (R)
  9. 9. R esponse E valuation C riteria i n S olid T umors: “RECIST” Working Group <ul><li>1995: International representation from different research organizations </li></ul><ul><li>Revisit definitions, assumptions, implications </li></ul><ul><li>Harmonize to the best standards </li></ul><ul><li>Simplify where possible </li></ul><ul><li>Update with new concepts </li></ul><ul><li>An ongoing process……… </li></ul>
  10. 10. RECIST Working Group 1995 - 99 <ul><li>Consensus approach </li></ul><ul><li>Reviewed different guidelines/criteria in use </li></ul><ul><li>Changes if possible supported by data/literature </li></ul><ul><li>First draft new criteria in 1997 </li></ul><ul><li>Consultation: ICH approach: </li></ul><ul><ul><li>US - Canada - Europe - Japan </li></ul></ul><ul><ul><li>Industry - Regulatory - Research Groups </li></ul></ul><ul><li>International Workshop to discuss/resolve issues October 1998 </li></ul><ul><li>Presentation: ASCO 1999, Publication 2000 </li></ul>
  11. 12. Response Evaluation Criteria in Solid Tumors (RECIST) P. Therasse et al, JNCI 2000 <ul><li>Major application intended for trials where response is primary endpoint </li></ul>
  12. 13. Key RECIST Elements <ul><li>Unidimensional measurement of longest diameters </li></ul><ul><li>Measurable lesion > 20 mm (10 mm Spiral CT) </li></ul><ul><li>Identify up to 10 measurable lesions; maximum 5 per organ. Follow sum of longest diameters (SLD) </li></ul><ul><li>Response Categories: </li></ul><ul><ul><li>PR = 30% decrease in SLD compared to baseline </li></ul></ul><ul><ul><li>PD = 20% increase in SLD compared to lowest value on study </li></ul></ul><ul><li>CT scan preferred imaging modality. No ultrasound. </li></ul>
  13. 14. Since 2000…… <ul><li>Many publications comparing RECIST to WHO and others*. </li></ul><ul><ul><li>With rare exceptions (e.g. mesothelioma) confirmed usefulness and reliability of unidimensional measurement </li></ul></ul><ul><li>A number of questions and issues have arisen… </li></ul>* See review in: Therasse et al. Eur J Cancer 2006
  14. 15. Issues Arising since RECIST Implementation <ul><li>Minimum number of lesions: Can fewer than 10 lesions be assessed? </li></ul><ul><li>Use of RECIST in randomized trials </li></ul><ul><li>Use of newer imaging technologies such as PET and MRI. </li></ul><ul><li>Use of RECIST in trials of non-cytotoxic drugs. </li></ul>
  15. 16. Minimum Number of lesions <ul><li>10 lesions (maximum 5 per organ site): </li></ul><ul><ul><li>Arbitrary choice. Unlikely to underestimate overall tumour burden. </li></ul></ul><ul><ul><li>But not evidence based. </li></ul></ul><ul><li>What kind of evidence could lead to change? </li></ul>
  16. 17. Example: 10 Lesions 255 132 171 248 SLD Liver Node Lung Site 20 20 20 25 10 30 22 24 30 9 40 25 30 40 8 25 17 15 22 7 20 13 15 30 6 10 0 5 10 5 8 0 5 10 4 42 15 20 27 3 30 15 20 34 2 30 15 17 20 1 Week 24 (mm) Week 16 (mm) Week 8 (mm) Baseline (mm) Lesion +93% -47% -31% Response PD PR PR
  17. 18. Example: 6 largest selected 182 110 129 186 SLD Liver Node Lung Site 20 20 20 25 10 30 22 24 30 9 40 25 30 40 8 25 17 15 22 7 20 13 15 30 6 10 0 5 10 5 8 0 5 10 4 42 15 20 27 3 30 15 20 34 2 30 15 17 20 1 Week 24 (mm) Week 16 (mm) Week 8 (mm) Baseline (mm) Lesion +65% -41% -31% Response PD PR PR
  18. 19. Example: 3 largest selected 90 53 65 104 SLD Liver Node Lung Site 20 20 20 25 10 30 22 24 30 9 40 25 30 40 8 25 17 15 22 7 20 13 15 30 6 10 0 5 10 5 8 0 5 10 4 42 15 20 27 3 30 15 20 34 2 30 15 17 20 1 Week 24 (mm) Week 16 (mm) Week 8 (mm) Baseline (mm) Lesion +70% -49% -38% Response PD PR PR
  19. 20. How Many Lesions? <ul><li>Actual patient data analyzed as on previous slides will help determine what “minimum” number of lesions can be </li></ul><ul><li> without changing the overall outcome or interpretation of a trial </li></ul><ul><li>Ongoing project at EORTC data centre to examine this: numerous trials and tumour measurement data from thousands of patients </li></ul>
  20. 21. RECIST in Randomized Clinical Trials (RCTs) <ul><li>Issues: </li></ul><ul><ul><li>Progression-Free Survival or Time to Progression are increasingly common primary endpoints in RCTs </li></ul></ul><ul><ul><li>Assessment of progression requires monitoring tumour size/number of lesions </li></ul></ul><ul><ul><li>Because of the need to assess disease progression, RECIST use in RCTs has become common </li></ul></ul>
  21. 22. RECIST in Randomized Trials <ul><li>This presents two issues: </li></ul><ul><ul><li>Can rigorous response assessment requirements be relaxed? </li></ul></ul><ul><ul><li>How to assess progression in patients who do not have measurable lesions? </li></ul></ul>
  22. 23. Measuring Objective Response in Phase III Trials <ul><li>RECIST paper indicates that when response is not primary endpoint , modifications may be allowed. e.g . </li></ul><ul><ul><li>Fewer than 10 lesions </li></ul></ul><ul><ul><li>No 4-week confirmation </li></ul></ul><ul><li>Such changes must be in protocol, not applied post-hoc. </li></ul>
  23. 24. RECIST in Randomized Trials <ul><li>Issues: </li></ul><ul><ul><li>Can rigorous response assessment requirements be relaxed? </li></ul></ul><ul><ul><li>How to assess progression in patients who do not have measurable lesions? </li></ul></ul>
  24. 25. Progression in Phase III Trials <ul><li>Important issue, since as noted PFS and TTP becoming common primary endpoints. </li></ul><ul><li>No problem if entry is restricted to patients with measurable lesions ! </li></ul><ul><li>But what about patients with non- measurable disease only? </li></ul>
  25. 26. Progression in Non-Measurable Disease <ul><li>Fundamental problem: how to measure an increase in that which is not measurable ? </li></ul><ul><li>Options: </li></ul><ul><ul><li>Count “new disease” only </li></ul></ul><ul><ul><li>Look for “unequivocal progression” of non-measurable lesions: subject to external review </li></ul></ul><ul><ul><li>Something else? </li></ul></ul><ul><ul><li>Go back to using overall survival? </li></ul></ul>
  26. 27. Progression in Non-Measurable Disease (2) <ul><li>This is not a problem unique to RECIST! </li></ul><ul><li>Need wider discussion on how to handle this with clinical researchers, regulatory officials and pharma. </li></ul><ul><li>At minimum today, for “critical” (new drug approval) trials where PFS is primary endpoint, regulatory agencies will require external review of imaging before considering the trial results acceptable. </li></ul>
  27. 28. What about newer imaging technologies (PET/CT and MRI)? <ul><li>Appendix I in RECIST paper </li></ul><ul><li>In principle PET/CT and MRI may be used to assess SIZE provided they: </li></ul><ul><ul><li>Can detect change in size from minimum baseline size that is representative of PR or PD </li></ul></ul><ul><ul><ul><li>e.g. if 10 mm lesion minimum at baseline, will modality detect 2-3 mm change? </li></ul></ul></ul>
  28. 29. What about Functional Changes? <ul><li>RECIST: </li></ul><ul><ul><li>Based on anatomical tumour size </li></ul></ul><ul><ul><li>Does not take into account phenomena such as tumour cavitation </li></ul></ul><ul><ul><li>Does not take into account metabolic function </li></ul></ul><ul><ul><li>Does not take into account blood flow parameters </li></ul></ul>
  29. 30. Publications: Proposed standards for function/flow: <ul><li>Young H, Baum R, Cremerius U, et al: Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Br J Cancer 1999; 35:1773-82 . </li></ul><ul><li>Leach MO, Brindle KM, Evelhoch JL, et al: Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials. Br J Radiol 2003;76 Spec No 1:S87-91. </li></ul>
  30. 31. Critical Question <ul><li>In terms of clinical benefit to an individual patient (survival, symptom improvement), or in terms of signaling that a new drug will improve survival ……. </li></ul><ul><li>what is meaning of a change induced by a new drug in measures of tumour blood flow or metabolism? </li></ul>
  31. 32. Are changes in flow and function meaningful in screening new drugs? <ul><li>To answer this we need to amass clinical data sets where: </li></ul><ul><ul><li>Agents selected for development because of changes in these measures (no obj. response) </li></ul></ul><ul><ul><li>And the results of randomized studies of these same drugs are known </li></ul></ul><ul><li>PTK787 story suggests more data needed before using these measures alone to screen new agents. </li></ul>
  32. 33. Are RECIST Applicable in Trials of Non-Cytotoxics?
  33. 34. Other proposed endpoints <ul><li>Stable disease above a minimum proportion and/or beyond a minimum duration </li></ul><ul><li>Progression free survival </li></ul><ul><li>Non-progression rates </li></ul><ul><li>Tumour shrinkage < PR </li></ul>
  34. 35. The Problem: <ul><li>With the exception of the last proposal (<PR shrinkage) all of the other endpoints are in fact RECIST categories ! </li></ul><ul><li>RECIST: </li></ul><ul><ul><li>DOES provide categories for describing how patients’ tumours change in size </li></ul></ul><ul><ul><li>DOES NOT state a minimum duration of stable disease (it DOES state it should be specified in each protocol) </li></ul></ul><ul><ul><li>DOES NOT provide guidance about what proportion of patients within those categories in a trial signals a new drug may be active </li></ul></ul>
  35. 36. So don’t be FAZED <ul><li>One does not need new “response criteria” for assessing non-cytotoxics </li></ul><ul><li>One may need to change the “usual” hypotheses that drive phase II design….so instead of a response rate of interest of 20% (typical for many cytotoxic phase II trials), we could: </li></ul><ul><ul><li>Look for PR + CR rate of 10% </li></ul></ul><ul><ul><li>Look for SD rate >50% </li></ul></ul><ul><ul><li>Look for CR + PR + SD rate >60% </li></ul></ul><ul><ul><li>(or whatever seems meaningful) </li></ul></ul>
  36. 37. Phase II Results Targeted Drugs Response Rate 30% Endometrium mTOR CCI779 17% H&N EGFR C225 (Cetuximab) VEGF C-kit, bcr-abl HER2 EGFR EGFR Target Breast Renal Colorectal Ovary GIST Breast NSCLC, H&N Endometrium Ovary NSCLC, H&N, Results single agent phase II Agent 5-10% 8% Not done 18% bevacizumab ~50% STI-571 10-20% trastuzumab 10-15% 12% 9% OSI774 (erlotinib) 10-15% ZD1839 (gefitinib)
  37. 38. RECIST in Trials of Targeted Drugs <ul><li>Major issue is regarding design (hypotheses, sample size, randomization etc.), not how one measures tumour size. </li></ul>
  38. 39. RECIST Revisited: SUMMARY <ul><li>In clinical cancer research, particularly phase II screening trials, standard criteria to describe change in burden of tumour are needed. </li></ul><ul><li>RECIST criteria widely adopted for this need. </li></ul><ul><li>However, some issues identified that need further work/resolution: </li></ul><ul><ul><li>Workload: can same information be obtained by following fewer lesions? </li></ul></ul><ul><ul><li>Assessing the role of functional imaging in screening new drugs </li></ul></ul><ul><ul><li>Determining how to assess progression in phase III trials when non-measurable disease only is present </li></ul></ul>
  39. 40. What is Happening Now? <ul><li>RECIST Working group has re-convened to examine these issues in systematic fashion </li></ul><ul><li>“ Revised” version of RECIST for assessment of anatomical tumour changes planned for 2008 will address several issues. </li></ul><ul><li>Role of functional imaging in drug development requires more systematic evaluation, longer follow-up to clarify if it can complement of replace RECIST in future. </li></ul>
  40. 41. Thank you for your attention!

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