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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


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


PHASE I


PHASE II


PHASE III


PHASE IV“Post-

Marketing” Studies • Expanded Treatment

Groups Under studied groups

(racial/gender) Long term benefit Long term risk Low frequency toxicity


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


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


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………


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


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


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


MEASURE THE LONGEST IN PLANE DIAMETER


MEASURABLE LESION

The round shape and sharp boundaries of this lung lesion (arrow) makeit ideally suited for linear measurement.


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)


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


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


Non measurable lesion


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


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


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


BEST MODALITY


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


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)


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


ENDOSCOPY AND LAPAROSCOPY Not yet been fully or widely validated

Requires expertise and restricted availability

Can be used to confirm CR by taking biopsy


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


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


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


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


LYMPH NODE ASSESSMENT

THE SOLID LINE IS THE SHORT AXIS


Short axis is 45.316


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


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)


CR

PR

PDSD

6 cm

3cm

9cm

5cm

7cm


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”


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


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


baseline Follow up


SPLITTING AND MERGING


MERGING


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


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


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


IMPORTANCE OF IV CONTRAST


CONTINUE MEASURING EVEN IF CAVITY DEVELOPS


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


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


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


PFS AND TTP Baseline estimation of expected PFS/TTP

without treatment

Methodology to be applied should be thoroughly described in the protocol


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)


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


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.


EXAMPLE: 10 LESIONS


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


EXAMPLE: 6 LARGEST SELECTED


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


EXAMPLE: 3 LARGEST SELECTED


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


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

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


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?


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?


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


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)


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


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


FUTURE?

WHO-Bidimensional

RECIST-Unidimensional

Volumetric


THANK YOU

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Health & Medicine

word response

measure response

response evaluation

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screening trials

daily practice

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