Response Evaluation

E. Eisenhauer ESMO ECLU Jul 2007E. Eisenhauer ESMO ECLU Jul 2007

Response Evaluation: Response Evaluation: Beyond RECISTBeyond RECIST

Elizabeth Eisenhauer MD FRCPCElizabeth Eisenhauer MD FRCPC

ESMO Conference LuganoESMO Conference Lugano

07 July 200707 July 2007


OutlineOutline

• Background: Background: – Why measure response?Why measure response?– Response criteria in cancer trials Response criteria in cancer trials

• Key aspects of RECISTKey aspects of RECIST• Implementation issues with RECISTImplementation issues with RECIST

– Minimum number of lesions Minimum number of lesions – RECIST in randomized trialsRECIST in randomized trials– Imaging with MRI and PETImaging with MRI and PET– Is RECIST applicable in trials of non-Is RECIST applicable in trials of non-

cytotoxics?cytotoxics?


Why Measure Response?Why Measure Response?

• The word “response” is used in a The word “response” is used in a number of contexts:number of contexts:

– To describe outcomes in daily practice To describe outcomes in daily practice (“my patient is responding to treatment”)(“my patient is responding to treatment”)

– As a As a surrogatesurrogate for benefit (e.g. in for benefit (e.g. in randomized trial)randomized trial)

– As the As the primaryprimary endpoint in phase II endpoint in phase II “screening” trials where a decision is being “screening” trials where a decision is being taken about future of drug or regimentaken about future of drug or regimen


Why Measure Response?Why Measure Response?

• The word “response” is used in a The word “response” is used in a number of contexts:number of contexts:

– To describe outcomes in daily practice To describe outcomes in daily practice (“my patient is responding to treatment”)(“my patient is responding to treatment”)

– As a As a surrogatesurrogate for benefit (e.g. in for benefit (e.g. in randomized trial)randomized trial)

– As the As the primaryprimary endpoint in phase II endpoint in phase II “screening” trials where a decision is “screening” trials where a decision is being taken about future of drug or being taken about future of drug or regimen.regimen. RECIST criteria developed RECIST criteria developed for thisfor this


Response Criteria in Clinical Response Criteria in Clinical TrialsTrials

• Clinical cancer research takes Clinical cancer research takes place in an international arena, place in an international arena, thus we need a common, thus we need a common, standard “language” to describe standard “language” to describe key methods and definitions for key methods and definitions for trial outcomes, such astrial outcomes, such as

– Toxic effects: terms and grades Toxic effects: terms and grades

– Time to event definitionsTime to event definitions

– Tumour response definitionsTumour response definitions



• In early drug development:In early drug development:

– Tumour Tumour shrinkageshrinkage has long been used to has long been used to provide a “signal” that new agents may be provide a “signal” that new agents may be effectiveeffective

– Anatomic-based criteria therefore required Anatomic-based criteria therefore required to describe and categorize patient outcomesto describe and categorize patient outcomes

– WHO/others defined CR, PR, SD, PD WHO/others defined CR, PR, SD, PD

• To be useful as endpoint, Response:To be useful as endpoint, Response:

– Must be Must be defineddefined consistently consistently

– Must be Must be implementedimplemented consistently consistently



• Mid-late 1990s: International working Mid-late 1990s: International working group began to meet to address some group began to meet to address some shortcomings of WHO. For example:shortcomings of WHO. For example:

– Complexity (bidimensional Complexity (bidimensional measurements)measurements)

– New technologies (CT)New technologies (CT)

– Silent on many areas so open to varying Silent on many areas so open to varying interpretation interpretation

– i.e. the “standard” was no longer i.e. the “standard” was no longer standardstandard


RResponse esponse EEvaluation valuation CCriteria riteria iin n SSolid olid TTumors: umors:

“RECIST” Working Group“RECIST” Working Group• 1995: International representation from 1995: International representation from

different research organizationsdifferent research organizations

• Revisit definitions, assumptions, Revisit definitions, assumptions, implicationsimplications

• HarmonizeHarmonize to the best standards to the best standards

• SimplifySimplify where possible where possible

• UpdateUpdate with new concepts with new concepts

• An ongoing process………An ongoing process………

EORTC: EORTC: P. TherasseP. TherasseM. Van M. Van

Glabbeke (S)Glabbeke (S)A.T. van A.T. van

OosteromOosteromJ. VerweijJ. Verweij

NCI US: NCI US: S. ArbuckS. ArbuckL. Rubinstein L. Rubinstein

(S)(S)M. ChristianM. ChristianR. KaplanR. Kaplan

NCICCTG:NCICCTG: E. Eisenhauer E. Eisenhauer NDDO:NDDO: J. WandersJ. WandersUK:UK: S. Gwyther S. Gwyther

(R)(R)


RResponse esponse EEvaluation valuation CCriteria riteria iin n SSolid olid TTumors: umors:

“RECIST” Working Group“RECIST” Working Group• 1995: International representation from 1995: International representation from

different research organizationsdifferent research organizations

• Revisit definitions, assumptions, Revisit definitions, assumptions, implicationsimplications

• HarmonizeHarmonize to the best standards to the best standards

• SimplifySimplify where possible where possible

• UpdateUpdate with new concepts with new concepts

• An ongoing process………An ongoing process………


RECIST Working Group 1995 - RECIST Working Group 1995 - 9999

• Consensus approachConsensus approach• Reviewed different guidelines/criteria in useReviewed different guidelines/criteria in use• Changes if possible supported by Changes if possible supported by

data/literature data/literature • First draft new criteria in 1997First draft new criteria in 1997• Consultation: ICH approach:Consultation: ICH approach:

– US - Canada - Europe - JapanUS - Canada - Europe - Japan– Industry - Regulatory - Research GroupsIndustry - Regulatory - Research Groups

• International Workshop to discuss/resolve International Workshop to discuss/resolve issues October 1998issues October 1998

• Presentation: ASCO 1999, Publication 2000Presentation: ASCO 1999, Publication 2000


Response Evaluation Criteria Response Evaluation Criteria in Solid Tumors (RECIST)in Solid Tumors (RECIST)

P. Therasse et al, JNCI 2000P. Therasse et al, JNCI 2000

• Major application intended for Major application intended for trials where trials where response is response is primary primary endpointendpoint


Key RECIST ElementsKey RECIST Elements

• UnidimensionalUnidimensional measurement of longest measurement of longest diametersdiameters

• Measurable lesion Measurable lesion >> 20 mm (10 mm Spiral CT) 20 mm (10 mm Spiral CT)• Identify up to 10 measurable lesions; maximum Identify up to 10 measurable lesions; maximum

5 per organ. Follow 5 per organ. Follow sum of longest diameterssum of longest diameters (SLD)(SLD)

• Response Categories:Response Categories:– PR = 30% decrease in SLD compared to baselinePR = 30% decrease in SLD compared to baseline– PD = 20% increase in SLD compared to lowest value PD = 20% increase in SLD compared to lowest value

on studyon study

• CT scan preferred imaging modality. No CT scan preferred imaging modality. No ultrasound.ultrasound.


Since 2000……Since 2000……

• Many publications comparing Many publications comparing RECIST to WHO and others*.RECIST to WHO and others*.

– With rare exceptions (e.g. With rare exceptions (e.g. mesothelioma) confirmed usefulness mesothelioma) confirmed usefulness and reliability of unidimensional and reliability of unidimensional measurementmeasurement

• A number of questions and issues A number of questions and issues have arisen…have arisen…

* See review in: Therasse et al. Eur J Cancer 2006* See review in: Therasse et al. Eur J Cancer 2006


Issues Arising since RECIST Issues Arising since RECIST ImplementationImplementation

1.1. Minimum number of lesions: Can Minimum number of lesions: Can fewer than 10 lesions be fewer than 10 lesions be assessed? assessed?

2.2. Use of RECIST in randomized trialsUse of RECIST in randomized trials

3.3. Use of newer imaging Use of newer imaging technologies such as PET and MRI. technologies such as PET and MRI.

4.4. Use of RECIST in trials of non-Use of RECIST in trials of non-cytotoxic drugs. cytotoxic drugs.


Minimum Number of Minimum Number of lesionslesions

• 10 lesions (maximum 5 per organ 10 lesions (maximum 5 per organ site):site):

– Arbitrary choice. Unlikely to Arbitrary choice. Unlikely to underestimateunderestimate overall tumour overall tumour burden.burden.

– But not evidence based.But not evidence based.

• What kind of evidence could lead What kind of evidence could lead to change?to change?


Example: 10 LesionsExample: 10 LesionsSiteSite LesionLesion BaselineBaseline

(mm)(mm)Week 8Week 8(mm)(mm)

Week 16Week 16(mm)(mm)


LungLung 11 2020 1717 1515 3030

22 3434 2020 1515 3030

33 2727 2020 1515 4242

44 1010 55 00 88

55 1010 55 00 1010

NodeNode 66 3030 1515 1313 2020

77 2222 1515 1717 2525

LiverLiver 88 4040 3030 2525 4040

99 3030 2424 2222 3030

1010 2525 2020 2020 2020

SLDSLD 248248 171171 132132 255255-31%-31% -47%-47% +93%+93%

ResponsResponsee

PRPR PRPR PDPD


Example: 6 largest Example: 6 largest selectedselected

SiteSite LesionLesion BaselineBaseline(mm)(mm)




LungLung 11 2020 1717 1515 3030

22 3434 2020 1515 3030

33 2727 2020 1515 4242

44 1010 55 00 88

55 1010 55 00 1010

NodeNode 66 3030 1515 1313 2020

77 2222 1515 1717 2525

LiverLiver 88 4040 3030 2525 4040

99 3030 2424 2222 3030

1010 2525 2020 2020 2020

SLDSLD 186186 129129 110110 182182-31%-31% -41%-41% +65%+65%

ResponsResponsee

PRPR PRPR PDPD


Example: 3 largest Example: 3 largest selectedselected

SiteSite LesionLesion BaselineBaseline(mm)(mm)




LungLung 11 2020 1717 1515 3030

22 3434 2020 1515 3030

33 2727 2020 1515 4242

44 1010 55 00 88

55 1010 55 00 1010

NodeNode 66 3030 1515 1313 2020

77 2222 1515 1717 2525

LiverLiver 88 4040 3030 2525 4040

99 3030 2424 2222 3030

1010 2525 2020 2020 2020

SLDSLD 104104 6565 5353 9090-38%-38% -49%-49% +70%+70%

ResponsResponsee

PRPR PRPR PDPD


How Many Lesions?How Many Lesions?

• ActualActual patient data analyzed as on patient data analyzed as on previous slides will help determine what previous slides will help determine what “minimum” number of lesions can be“minimum” number of lesions can be

withoutwithout changing the overall outcome changing the overall outcome oror interpretation of a trial interpretation of a trial

• Ongoing project at EORTC data centre Ongoing project at EORTC data centre to examine this: numerous trials and to examine this: numerous trials and tumour measurement data from tumour measurement data from thousands of patientsthousands of patients


RECIST in Randomized RECIST in Randomized Clinical Trials (RCTs)Clinical Trials (RCTs)

• Issues:Issues:

– Progression-Free Survival or Time to Progression-Free Survival or Time to Progression are increasingly common Progression are increasingly common primaryprimary endpoints in RCTs endpoints in RCTs

– Assessment of progression requires Assessment of progression requires monitoring tumour size/number of monitoring tumour size/number of lesionslesions

– Because of the need to assess disease Because of the need to assess disease progression, RECIST use in RCTs has progression, RECIST use in RCTs has become commonbecome common


RECIST in Randomized RECIST in Randomized TrialsTrials

• This presents two issues:This presents two issues:

– Can rigorous response assessment Can rigorous response assessment requirements be relaxed?requirements be relaxed?

– How to assess progression in How to assess progression in patients who do not have patients who do not have measurable lesions?measurable lesions?


Measuring Objective Measuring Objective Response in Phase III TrialsResponse in Phase III Trials

• RECIST paper indicates that RECIST paper indicates that when response is when response is not primary not primary endpointendpoint, modifications may be , modifications may be allowed. allowed. e.ge.g..

– Fewer than 10 lesionsFewer than 10 lesions

– No 4-week confirmationNo 4-week confirmation

• Such changes must be in Such changes must be in protocol, not applied post-hoc.protocol, not applied post-hoc.


RECIST in Randomized RECIST in Randomized TrialsTrials

• Issues:Issues:

– Can rigorous response assessment Can rigorous response assessment requirements be relaxed?requirements be relaxed?

– How to assess progression in How to assess progression in patients who do not have patients who do not have measurable lesions?measurable lesions?


Progression in Phase III Progression in Phase III TrialsTrials

• Important issue, since as noted Important issue, since as noted PFS and TTP becoming common PFS and TTP becoming common primary endpoints.primary endpoints.

• No problem if entry is restricted No problem if entry is restricted to patients to patients with measurable with measurable lesionslesions!!

• But what about patients with But what about patients with non- measurable disease only?non- measurable disease only?


Progression in Progression in Non-Measurable DiseaseNon-Measurable Disease

• Fundamental problem: how to Fundamental problem: how to measuremeasure an increase in that which an increase in that which is is not measurablenot measurable??

• Options:Options:– Count “new disease” onlyCount “new disease” only– Look for “unequivocal progression” of Look for “unequivocal progression” of

non-measurable lesions: subject to non-measurable lesions: subject to external reviewexternal review

– Something else? Something else? – Go back to using overall survival?Go back to using overall survival?


Progression in Progression in Non-Measurable Disease (2)Non-Measurable Disease (2)

• This is not a problem unique to RECIST! This is not a problem unique to RECIST!

• Need wider discussion on how to handle Need wider discussion on how to handle this with clinical researchers, regulatory this with clinical researchers, regulatory officials and pharma. officials and pharma.

• At minimum today, for “critical” (new At minimum today, for “critical” (new drug approval) trials where PFS is drug approval) trials where PFS is primary endpoint, regulatory agencies primary endpoint, regulatory agencies will require external review of imaging will require external review of imaging before considering the trial results before considering the trial results acceptable.acceptable.


What about newer imaging What about newer imaging technologies (PET/CT and technologies (PET/CT and

MRI)?MRI)?• Appendix I in RECIST paperAppendix I in RECIST paper

• In principle PET/CT and MRI may In principle PET/CT and MRI may be used to assess SIZE provided be used to assess SIZE provided they:they:

– Can detect change in size from Can detect change in size from minimum baseline size that is minimum baseline size that is representative of PR or PDrepresentative of PR or PD

•e.g. if 10 mm lesion minimum at e.g. if 10 mm lesion minimum at baseline, will modality detect 2-3 mm baseline, will modality detect 2-3 mm change?change?


What about Functional What about Functional Changes?Changes?

• RECIST: RECIST:

– Based on anatomical tumour Based on anatomical tumour sizesize

– Does Does notnot take into account take into account phenomena such as tumour phenomena such as tumour cavitationcavitation

– Does Does notnot take into account take into account metabolic functionmetabolic function

– Does Does notnot take into account blood take into account blood flow parametersflow parameters


Publications: Publications: Proposed standards for Proposed standards for

function/flow:function/flow:• Young H, Baum R, Cremerius U, et al: Young H, Baum R, Cremerius U, et al:

Measurement of clinical and subclinical tumour Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 positron emission tomography: review and 1999 EORTC recommendations. European Organization EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) for Research and Treatment of Cancer (EORTC) PET Study Group. PET Study Group. Br J Cancer 1999; 35:1773-82Br J Cancer 1999; 35:1773-82..

• Leach MO, Brindle KM, Evelhoch JL, et al: Leach MO, Brindle KM, Evelhoch JL, et al: Assessment of antiangiogenic and antivascular Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for therapeutics using MRI: recommendations for appropriate methodology for clinical trials.appropriate methodology for clinical trials.Br J Radiol 2003;76 Spec No 1:S87-91.Br J Radiol 2003;76 Spec No 1:S87-91.


Critical QuestionCritical Question

• In terms of clinical benefit to an In terms of clinical benefit to an individual patientindividual patient (survival, (survival, symptom improvement), or in symptom improvement), or in terms of terms of signaling that a new signaling that a new drug will improve survivaldrug will improve survival ……. …….

what is what is meaningmeaning of a change of a change induced by a new drug in induced by a new drug in measures of tumour blood measures of tumour blood flow or metabolism?flow or metabolism?


Are changes in flow and function Are changes in flow and function meaningful in screening new meaningful in screening new

drugs?drugs?• To answer this we need to amass To answer this we need to amass

clinical data sets where:clinical data sets where:

– Agents selected for development Agents selected for development because because of changes in these measures of changes in these measures (no obj. (no obj. response)response)

– And the results of randomized studies of And the results of randomized studies of these same drugs are knownthese same drugs are known

• PTK787 story suggests more data PTK787 story suggests more data needed before using these measures needed before using these measures alone to alone to screenscreen new agents. new agents.


Are RECIST Applicable in Are RECIST Applicable in Trials of Non-Cytotoxics?Trials of Non-Cytotoxics?


Other proposed endpointsOther proposed endpoints

• Stable disease above a minimum Stable disease above a minimum proportion and/or beyond a proportion and/or beyond a minimum durationminimum duration

• Progression free survivalProgression free survival

• Non-progression ratesNon-progression rates

• Tumour shrinkage < PRTumour shrinkage < PR


The Problem:The Problem:• With the exception of the last proposal With the exception of the last proposal

(<PR shrinkage) (<PR shrinkage) all of the other all of the other endpoints are in fact RECIST categoriesendpoints are in fact RECIST categories!!

• RECIST:RECIST:– DOES provide categories for describing how DOES provide categories for describing how

patients’ tumours change in sizepatients’ tumours change in size

– DOES NOT state a minimum duration of DOES NOT state a minimum duration of stable disease (it DOES state it should be stable disease (it DOES state it should be specified in each protocol)specified in each protocol)

– DOES NOT provide guidance about what DOES NOT provide guidance about what proportion of patients within those proportion of patients within those categories in a trial categories in a trial signals a new drug may signals a new drug may be activebe active


So don’t be FAZEDSo don’t be FAZED• One does not need new “response criteria” One does not need new “response criteria”

for assessing non-cytotoxicsfor assessing non-cytotoxics

• One One maymay need to change the “usual” need to change the “usual” hypotheses that drive phase II design….so hypotheses that drive phase II design….so instead of a response rate of interest of instead of a response rate of interest of 20% (typical for many cytotoxic phase II 20% (typical for many cytotoxic phase II trials), we could:trials), we could:– Look for PR + CR rate of 10%Look for PR + CR rate of 10%

– Look for SD rate >50%Look for SD rate >50%

– Look for CR + PR + SD rate >60%Look for CR + PR + SD rate >60%

– (or whatever seems meaningful)(or whatever seems meaningful)


Phase II Results Targeted Phase II Results Targeted DrugsDrugs

AgentAgent TargetTarget Results single agent Results single agent phase IIphase II

Response RateResponse Rate

ZD1839 ZD1839 (gefitinib)(gefitinib)

EGFREGFR NSCLC, NSCLC, H&N, H&N,

10-15%10-15%

OSI774 OSI774 (erlotinib)(erlotinib)

EGFREGFR NSCLC, H&NNSCLC, H&NEndometriuEndometriummOvaryOvary

10-15%10-15%12%12%9%9%

C225 C225 (Cetuximab)(Cetuximab)

EGFREGFR H&NH&N 17%17%

CCI779CCI779 mTORmTOR EndometriuEndometriumm

30%30%

trastuzumabtrastuzumab HER2HER2 BreastBreast 10-20%10-20%

STI-571STI-571 C-kit, bcr-C-kit, bcr-ablabl

GISTGIST ~50% ~50%

bevacizumabbevacizumab VEGFVEGF BreastBreastRenalRenalColorectalColorectalOvaryOvary

5-10%5-10%8%8%Not doneNot done18%18%


RECIST in Trials of Targeted RECIST in Trials of Targeted DrugsDrugs

• Major issue is regarding Major issue is regarding designdesign (hypotheses, sample size, (hypotheses, sample size, randomization etc.), not how one randomization etc.), not how one measures tumour size.measures tumour size.


RECIST Revisited: RECIST Revisited: SUMMARYSUMMARY

• In clinical cancer research, particularly phase In clinical cancer research, particularly phase II screening trials, standard criteria to describe II screening trials, standard criteria to describe change in burden of tumour are needed. change in burden of tumour are needed.

• RECIST criteria widely adopted for this need.RECIST criteria widely adopted for this need.

• However, some issues identified that need However, some issues identified that need further work/resolution:further work/resolution:

– Workload: can same information be obtained Workload: can same information be obtained by following fewer lesions?by following fewer lesions?

– Assessing the role of functional imaging in Assessing the role of functional imaging in screening new drugsscreening new drugs

– Determining how to assess progression in Determining how to assess progression in phase III trials when non-measurable disease phase III trials when non-measurable disease only is presentonly is present


What is Happening Now?What is Happening Now?

• RECIST Working group has re-convened RECIST Working group has re-convened to examine these issues in systematic to examine these issues in systematic fashionfashion

• ““Revised” version of RECIST for Revised” version of RECIST for assessment of anatomical tumour assessment of anatomical tumour changes planned for 2008 will address changes planned for 2008 will address several issues.several issues.

• Role of functional imaging in drug Role of functional imaging in drug development requires more systematic development requires more systematic evaluation, longer follow-up to clarify if it evaluation, longer follow-up to clarify if it can complement of replace RECIST in can complement of replace RECIST in future.future.


Thank you for your Thank you for your attention!attention!

Response Evaluation

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