Response Evaluation
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Response Evaluation

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  • non-measurable lesions can be used to evaluate OS? thanks
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Response Evaluation Response Evaluation Presentation Transcript

  • Response Evaluation: Beyond RECIST Elizabeth Eisenhauer MD FRCPC ESMO Conference Lugano 07 July 2007
  • 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?
  • 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
  • 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
  • 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
  • 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
  • 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
  • R esponse E valuation C riteria i n S olid T umors: “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………
    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)
  • R esponse E valuation C riteria i n S olid T umors: “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………
  • 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
  •  
  • Response Evaluation Criteria in Solid Tumors (RECIST) P. Therasse et al, JNCI 2000
    • Major application intended for trials where response is primary endpoint
  • 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.
  • 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
  • Issues Arising since RECIST Implementation
    • Minimum number of lesions: Can fewer than 10 lesions be assessed?
    • Use of RECIST in randomized trials
    • Use of newer imaging technologies such as PET and MRI.
    • Use of RECIST in trials of non-cytotoxic drugs.
  • 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?
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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?
  • 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.
  • RECIST in Randomized Trials
    • Issues:
      • Can rigorous response assessment requirements be relaxed?
      • How to assess progression in patients who do not have measurable lesions?
  • 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 non- measurable disease only?
  • 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 non-measurable lesions: subject to external review
      • Something else?
      • Go back to using overall survival?
  • 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.
  • 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?
  • 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
  • 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.
  • 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?
  • 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.
  • Are RECIST Applicable in Trials of Non-Cytotoxics?
  • Other proposed endpoints
    • Stable disease above a minimum proportion and/or beyond a minimum duration
    • Progression free survival
    • Non-progression rates
    • Tumour shrinkage < PR
  • 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
  • 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)
  • 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)
  • RECIST in Trials of Targeted Drugs
    • Major issue is regarding design (hypotheses, sample size, randomization etc.), not how one measures tumour size.
  • 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
  • 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.
  • Thank you for your attention!