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Response Evaluation 

Response Evaluation

 

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

   
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