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Transcript of Full recist violet
RESPONSE EVALUATION IN SOLID TUMORS
PRESENTER: DR.B.SATHISH(JR,1ST Yr RT)
MODERATOR:DR.ASHUTOSH MUKHERJEE,Asst Prof RT
E. Eisenhauer ESMO ECLU Jul 2007
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”) and make decisions about continuing therapy
As a surrogate for benefit (e.g. in randomized trial)
As the primary endpoint in phase II “screening” trials
E. Eisenhauer ESMO ECLU Jul 2007
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
PHASE I
E. Eisenhauer ESMO ECLU Jul 2007
PHASE II
E. Eisenhauer ESMO ECLU Jul 2007
E. Eisenhauer ESMO ECLU Jul 2007
E. Eisenhauer ESMO ECLU Jul 2007
PHASE III
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E. Eisenhauer ESMO ECLU Jul 2007
PHASE IV“Post-
Marketing” Studies • Expanded Treatment
Groups Under studied groups
(racial/gender) Long term benefit Long term risk Low frequency toxicity
E. Eisenhauer ESMO ECLU Jul 2007
HISTORY Early attempts 1960s
Pre imaging era –blood was used to assess tumor response
WHO first published tumor response criteria for solid tumors in 1981
RECIST was presented in 1999 to ASCO and published in 2000
RECIST VERSION 1.1 published in October 2008
E. Eisenhauer ESMO ECLU Jul 2007
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 the standard
E. Eisenhauer ESMO ECLU Jul 2007
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
RECIST VERSION 1.1 Response Evaluation Criteria in Solid Tumors
• Standardized repeatable method for measuring response to therapy for solid tumors
• NOT EQUIVALENT TO A CLINICAL READ!!! RECIST is a combination of both qualitative and
quantitative assessment Based on concept of target lesions and non-target
lesions• Target lesions are quantitatively assessed• Non-target lesions are qualitatively assessed
E. Eisenhauer ESMO ECLU Jul 2007
KEY RECIST ELEMENTS One-dimensional measurement of longest
diameters Measurable lesion > 10 mm (5 mm Spiral CT) Identify up to 5 measurable lesions; maximum
2 per organ. Follow sum of longest diameters (SLD)
The “SLD” is a quantitative assessment Major application intended for trials where
response is primary endpoint Separate criteria used for malignant
lymphoma so RECIST not used Can be used in brain tumors but separate
criteria are also published
E. Eisenhauer ESMO ECLU Jul 2007
TARGET LESIONS• Target lesions are chosen based on 3 factors:
Must be EASILY (and reproducibly) measurable Must be representative of the disease (clearly metastasis) Must be representative of distribution (choose measurable
lesions from all involved organs) Target lesions must be measurable
Definition of Measurable Lesions Size Matters
Conventional CT or MRI (non-spiral): If slice collimation <10mm, minimum lesion size is 20 mm If slice collimation >10mm, minimum lesion size is 2 x
collimationex. Slice collimation = 15mm, minimum lesion size = 30mm
Spiral CT If slice collimation <5mm, minimum lesion size is 10 mm If slice collimation >5mm, minimum lesion size is 2 x collimation
ex. Slice collimation = 7mm, minimum lesion size = 14mm
16
E. Eisenhauer ESMO ECLU Jul 2007
MEASURE THE LONGEST IN PLANE DIAMETER
E. Eisenhauer ESMO ECLU Jul 2007
MEASURABLE LESION
The round shape and sharp boundaries of this lung lesion (arrow) makeit ideally suited for linear measurement.
E. Eisenhauer ESMO ECLU Jul 2007
TARGET LESIONSTarget lesions must be reproducibly measurableDefinition of reproducibly measurable lesions Consistency across time points
Pick lesions with well defined edges or margins Always measure longest diameter Measure lesions on same phase or same sequence (MRI) Only measure lesions that are definitely metastases
(If unsure don’t measure) Pick lesions that are stable in position, try to avoid mobile
lesions (Avoid mesenteric masses that change in position)
E. Eisenhauer ESMO ECLU Jul 2007
E. Eisenhauer ESMO ECLU Jul 2007
TARGET LESIONS
Target lesions should represent distribution of disease
Representative of disease throughout body Pick lesions from different areas of the body
Do not choose > 2 lesions in any one organ or anatomic location Organs are well defined
For lymphoma choose nodes from different nodal stations
E. Eisenhauer ESMO ECLU Jul 2007
NON – TARGET LESIONS All aspects of disease not chosen as Target Lesions
All non-measurable lesions(LD < 10 mm and LN 10-14mm in short axis)
Measurable lesions that were not chosen as target lesions Lesions that may be (but not definitely) metastases
Non- measurable lesions
Not suitable for accurate repeated measurements• Ascites • Pericardial effusion • Leptomeningeal disease• Pleural effusions • Inflammatory breast disease• Cystic lesions • Lymphangitis cutis/pulmonis• Bone lesions • Brain lesions• Irradiated lesions • Ground glass lung lesions
E. Eisenhauer ESMO ECLU Jul 2007
Non measurable lesion
E. Eisenhauer ESMO ECLU Jul 2007
SPECIAL CONSIDERATIONS Lytic bone lesions with soft tissue
component which meets the definition of measurability by CT /MRI can be considered measurable
Blastic bone lesions are not measurable Simple cysts are not considered
malignant so not taken as targets Cystic metastases meeting the criteria
can be considered but if non cystic lesions are present they are preferred as targets
E. Eisenhauer ESMO ECLU Jul 2007
CLINICAL EVALUATION Considered measurable only if
superficial(e.g. skin nodules and lymph nodes)
10mm minimum size by caliper measurement{if immeasurable by calipers it is termed as non-measurable}
Documentation with color photo and ruler is needed
Imaging is always better than clinical assessment
E. Eisenhauer ESMO ECLU Jul 2007
CXR Measurable lesion
20 mm minimum size Clearly defined Surrounded by aerated lungFull inspiration, PA view with constant tube-
chest distance at every follow up
E. Eisenhauer ESMO ECLU Jul 2007
BEST MODALITY
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CT SCAN If 5mm slice thickness then the lesion should be
minimum 10mm Minimum size of lesion>=double slice thickness LD is selected in axial plane only Para spinal tumors are better measured in
coronal/sagittal plane Lesions bordering chest wall and mediastinal
lesions(don’t use CXR as slight motion can affect interpretation)
Oral and iv contrast to accentuate bowel/vessels against soft tissue mass is routinely done
Most abdominal images are taken in the portal venous phase
E. Eisenhauer ESMO ECLU Jul 2007
MRI Complex issue MRI Scanners vary in images produced
based on Magnet strength Coil design Patient cooperation Motion artifacts
Use same scanner and same anatomical plane
As far as possible use a CT scan IOC for follow up of breast lesions in NACT
(not CT or mammogram)
E. Eisenhauer ESMO ECLU Jul 2007
USG Not used in clinical trials because
interpretation is subjective Alternative to clinical measurements for
Superficial palpable lymph nodes Subcutaneous lesions Thyroid nodules To confirm disappearance of superficial lesions
assessed clinically If there is a para aortic node and distended
bowel USG wont detect it and so downstage the disease
Reproducibility of entire examination at later date not accurate
E. Eisenhauer ESMO ECLU Jul 2007
ENDOSCOPY AND LAPAROSCOPY Not yet been fully or widely validated
Requires expertise and restricted availability
Can be used to confirm CR by taking biopsy
E. Eisenhauer ESMO ECLU Jul 2007
TUMOR MARKERS
Cant be used alone to assess response Specific guidelines for PSA and CA125
have been published Gynecological cancer intergroup has
developed CA125 progression criteria which are to be integrated with objective tumor assessment for use in first line trials in ovarian cancer
E. Eisenhauer ESMO ECLU Jul 2007
HPE To differentiate partial vs. complete
response in rare cases(e.g. residual tumors can be benign in germ cell tumors)
Worsening effusion in stable disease or responded disease needs cytology to differentiate progression vs. drug induced e.g. taxane compunds
E. Eisenhauer ESMO ECLU Jul 2007
MEASURING LESIONS Baseline Scan – Initial Review
Determine if a single measurable lesion is present Once single lesion is found, confirm the neoplastic
nature by biopsy Baseline assessment never >4weeks before the
beginning of treatment Baseline scan – Full Review
Determine target lesions and non-target lesions Target lesions
Record site and longest diameter Measure longest diameter (LD) on slice where the lesion
is largest Use magnification and appropriate window/level
Non-target lesions Record site and description Will be assessed qualitatively in the future
E. Eisenhauer ESMO ECLU Jul 2007
MALIGNANT LYMPH NODES To be considered pathological a lymph
node must be >=15mm in short axis by CT scan with slice thickness not more than 5 mm
Only short axis is measured at baseline and follow up(e.g. for an abdominal node 20*30 mm size 20mm is taken as short axis)
Multiple lesions in single organ can be recorded as single item e.g. multiple pelvic nodes/multiple liver mets
E. Eisenhauer ESMO ECLU Jul 2007
LYMPH NODE ASSESSMENT
THE SOLID LINE IS THE SHORT AXIS
E. Eisenhauer ESMO ECLU Jul 2007
Short axis is 45.316
E. Eisenhauer ESMO ECLU Jul 2007
EXAMPLE: 10 LESIONS
Site Lesion Baseline(mm)
Week 8(mm)
Week 16(mm)
Week 24(mm)
Lung 1 20 17 15 30
2 34 20 15 30
3 27 20 15 42
4 10 5 0 8
5 10 5 0 10
Node 6 30 15 13 20
7 22 15 17 25
Liver 8 40 30 25 40
9 30 24 22 30
10 25 20 20 20
SLD 248 171 132 255
-31% -47% +93%
Response
PR PR PD
E. Eisenhauer ESMO ECLU Jul 2007
TUMOR RESPONSE - TARGET LESIONS
Complete response (CR): Disappearance of all target lesions and any pathological LN(target or non target must have <10 mm short axis)
Partial response (PR): >= 30% decrease in the SLD taking as reference the baseline SLD
Progression (PD): >= 20% increase in the SLD taking as reference the smallest SLD since beginning of treatment and also a minimum absolute increase of 5mm
Stable decrease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest SLD since beginning of treatment
Unknown (UN): If one or more unknown is present and the SLD is not indicative of PD (explanatory comments required)
E. Eisenhauer ESMO ECLU Jul 2007
CR
PR
PDSD
6 cm
3cm
9cm
5cm
7cm
E. Eisenhauer ESMO ECLU Jul 2007
TUMOR RESPONSE – NON-TARGET LESIONS
Complete Response (CR): Disappearance of all lesions and normalization of all tumor marker levels and lymph nodes <10 mm in short axis
Non CR/Non-PD :persistence of one or more lesions and/or maintenance of tumor markers above normal limits
Progression (PD):appearance of new lesions and/or unequivocal progression of existing lesions
Unknown (UN): If “not assessed” or “not imaged”
E. Eisenhauer ESMO ECLU Jul 2007
TUMOR RESPONSE – NEW LESIONS
Unequivocal New Lesions = Progression (PD)
• Any new malignant lesion in the same or different site
• Any re-appearing lesion PET scan( FDG uptake period of 60 min prior
to imaging) -ve baseline but +ve follow up –PD No baseline scan and +ve follow up
If it is at a new site then –consider PD If not at the same site additional follow up with CT
to confirm PD If follow up CT is negative then it is not PD
Best overall response is the best response from the start of treatment until disease progression/recurrence
E. Eisenhauer ESMO ECLU Jul 2007
FOLLOW-UP: TARGET LESIONS On follow-up scans, once a lesion is identified as
Target: Must continue to measure even if LD falls below size
criteria Same method(e.g.CT) of assessment as baseline
should be used Measure LD regardless of location (slice) or
orientation on prior scan Choose slice where lesion is largest, even if different
than baseline Measure LD regardless of poor image quality or poorly
defined lesion boundaries (i.e., if target lesion is imaged, LD must be measured)
If a target lesion is visible but too small to measure, list as “5mm”
If radiologist feels lesion has disappeared record as 0 mm If lesion is not imaged, enter “Unknown” (outside
FOV) If “unknown” is entered, comments are required
E. Eisenhauer ESMO ECLU Jul 2007
baseline Follow up
E. Eisenhauer ESMO ECLU Jul 2007
SPLITTING AND MERGING
E. Eisenhauer ESMO ECLU Jul 2007
MERGING
E. Eisenhauer ESMO ECLU Jul 2007
FOLLOW-UP SCANS New lesions seen on follow-up:
Any lesion that appears after baseline (including new lesions in irradiated areas)
Any lesions that re-appear will be considered new lesions
If a lesion reappears after CR then it is PD
If lesion reappears in PR/SD measure its LD and add to SLD to assess response
No miminum diameter is needed for a new lesion and if equivocal repeat CT in the next visit and get a radiologist opinion
E. Eisenhauer ESMO ECLU Jul 2007
MISSING ASSESSMENTS AND IN EVALUABLE DESIGNATION
No imaging done at protocol specified time point-non evaluable(NE)
Not all lesions measured at follow up-NE(conditions apply)
Lost to follow-up : in evaluable
E. Eisenhauer ESMO ECLU Jul 2007
SPECIAL SCENARIOS If global deterioration of health requiring Rx
discontinuation then it is classified as symptomatic deterioration It is not an objective response but a reason to
discontinue therapy If u cant differentiate normal tissue from
residual disease/scarring-- biopsy/PET scan is done before calling it as complete response
If equivocal findings at follow up wait till next follow up to confirm PD,SD or PR
If solid lesion becomes necrotic still measure LD and make a note of the necrosis
E. Eisenhauer ESMO ECLU Jul 2007
IMPORTANCE OF IV CONTRAST
E. Eisenhauer ESMO ECLU Jul 2007
CONTINUE MEASURING EVEN IF CAVITY DEVELOPS
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FREQUENCY OF REEVALUATION Protocol specific
Which organ?How often?
Goal of trial - response or TTP/PFS?Routine calendar scheduled re-
evaluation
In phase 2 studies follow up every 6-8 weeks is an acceptable norm
E. Eisenhauer ESMO ECLU Jul 2007
CONFIRMATION OF RESPONSE
Particularly useful in non randomized trials where response in the primary end point
To ensure that response is not a measurement error
If criteria for CR or PR are met reassess in no less than 4 weeks to confirm response
If SD then criteria must be met at least once after study entry at a minimum interval defined by study protocol
E. Eisenhauer ESMO ECLU Jul 2007
DURATION OF OVERALL RESPONSE From the time the criteria for CR/PR is met
first till the day 1 of objectively documented PD or recurrence
Duration of SD- time from start of Rx/date of randomization till the criteria for PD are met
The response is reviewed by a panel of experts independent of the study
E. Eisenhauer ESMO ECLU Jul 2007
PFS AND TTP Baseline estimation of expected PFS/TTP
without treatment
Methodology to be applied should be thoroughly described in the protocol
E. Eisenhauer ESMO ECLU Jul 2007
REPORTING RESULTS1. CR2. PR3. SD4. PD5. Inevaluable for response
1. Early death from malignancy2. Early death from toxicity3. Early death due to some other cause4. Unknown(not assessable,insufficent data)
6. (1- 4 are called eligible patients to calculate response rate)
E. Eisenhauer ESMO ECLU Jul 2007
TUMOR RESPONSE – SUMMARIZED
Target LesionsNon-target
LesionsNew Lesions
Overall Response
CR CR No CR
CRSD(Non-CR/
non-PD)No PR
PR CR or SD No PR
SD CR or SD No SD
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes (PD) PD
E. Eisenhauer ESMO ECLU Jul 2007
ISSUES ARISING SINCE RECIST IMPLEMENTATION
1. Minimum number of lesions: Can fewer than 5 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
EXAMPLE: 10 LESIONS
Site Lesion Baseline(mm)
Week 8(mm)
Week 16(mm)
Week 24(mm)
Lung 1 20 17 15 30
2 34 20 15 30
3 27 20 15 42
4 10 5 0 8
5 10 5 0 10
Node 6 30 15 13 20
7 22 15 17 25
Liver 8 40 30 25 40
9 30 24 22 30
10 25 20 20 20
SLD 248 171 132 255
-31% -47% +93%
Response
PR PR PD
E. Eisenhauer ESMO ECLU Jul 2007
EXAMPLE: 6 LARGEST SELECTED
Site Lesion Baseline(mm)
Week 8(mm)
Week 16(mm)
Week 24(mm)
Lung 1 20 17 15 30
2 34 20 15 30
3 27 20 15 42
4 10 5 0 8
5 10 5 0 10
Node 6 30 15 13 20
7 22 15 17 25
Liver 8 40 30 25 40
9 30 24 22 30
10 25 20 20 20
SLD 186 129 110 182
-31% -41% +65%
Response
PR PR PD
E. Eisenhauer ESMO ECLU Jul 2007
EXAMPLE: 3 LARGEST SELECTED
Site Lesion Baseline(mm)
Week 8(mm)
Week 16(mm)
Week 24(mm)
Lung 1 20 17 15 30
2 34 20 15 30
3 27 20 15 42
4 10 5 0 8
5 10 5 0 10
Node 6 30 15 13 20
7 22 15 17 25
Liver 8 40 30 25 40
9 30 24 22 30
10 25 20 20 20
SLD 104 65 53 90
-38% -49% +70%
Response
PR PR PD
E. Eisenhauer ESMO ECLU Jul 2007
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
MEASURING OBJECTIVE RESPONSE IN PHASE III TRIALS
If objective response is the end point then use RECIST 1.1
If objective response is not the primary endpoint, then method of reporting results should be pre-specified in the protocol
E. Eisenhauer ESMO ECLU Jul 2007
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!
What about patients with non-measurable disease only?
E. Eisenhauer ESMO ECLU Jul 2007
PROGRESSION IN NON-MEASURABLE DISEASE
Fundamental problem: how to measure an increase in that which is not measurable?
Options:Count “new disease” onlyLook for “unequivocal progression” of non-
measurable lesions: subject to external reviewSomething else? Go back to using overall survival?
E. Eisenhauer ESMO ECLU Jul 2007
WHAT ABOUT FUNCTIONAL CHANGES?
RECIST:
Based on anatomical tumour size
Does not take into account metabolic function
Does not take into account blood flow parameters
E. Eisenhauer ESMO ECLU Jul 2007
ARE RECIST APPLICABLE IN TRIALS OF NON-CYTOTOXICS?
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
WHAT HAS CHANGED IN RECIST 1.1
RECIST 1.0 RECIST 1.1
Measuring tumor burden
10 targets5 per organ
For response: 5 targets(2 per organ)
Lymph node Measure long axis as for other lesions. Silent on normal size
Measure short axis. Define normal size.
Progression definition
20% increase in sum
20% increase and at least 5 mm absolute increase
Non-measurable disease PD
“must be unequivocal”
Expanded definition to convey impact on overall burden of disease. Examples.
Confirmation of objective response
required Required when response primary endpoint—but not otherwise
New lesions -- New section which includes comment on FDG PET interpretation
E. Eisenhauer ESMO ECLU Jul 2007
E. Eisenhauer ESMO ECLU Jul 2007
LIMITATIONS OF RECIST GUIDELINES
Tumor morphology
Confluent, Irregular borders Unusual configuration; Circumferential (e.g. mesothelioma) Lesion length > 1.5-2 times lesion width
Discordant results due to RECIST technique Uni-dimensional measurement Shape changes may confound results
Non-spherical, asymmetric tumor growth Tumor size: Sub-centimeter tumors Choosing representative tumor burden
Problematic when tumor burden is substantial Unpredictable Tumor Behavior
Differential tumor shrinkage/growth
E. Eisenhauer ESMO ECLU Jul 2007
FUTURE?
WHO-Bidimensional
RECIST-Unidimensional
Volumetric
E. Eisenhauer ESMO ECLU Jul 2007
THANK YOU