CLINICAL RESPONSE ASSESSMENT

Dr. Varun GoelMedical oncologist

Rajiv gandhi cancer institute

INTRODUCTION

• Evaluating the efficacy of anti-cancer treatment is important for medical decisions

• in practice as well as in clinical trials.

• The methodology used to evaluate the response has evolved substantially over the past decades

• complete subjective evaluation complex set of objective criteria attempting to standardize the response evaluation process

INTRODUCTION• Early attempts were made in the early 1960s

• Zubrod CG, et al. J Chronic Dis 1960;11:7–33

• Tumour shrinkage

• In 1976, 16 experienced oncologists, gathered to decide what would be considered a reliable measure of response to therapy.

• Measurement tool - product of the perpendicular diameters of a sphere.

• When two investigators measure same sphere

• ideally there should be no difference.

– Measurement differed by 50% • 7.8% of the time

– Differences of 25% • 19% of the time

–unacceptably high

• Moertel and Hanley recommended: – 50% reduction criterion should be applied in

clinical settings and – that the investigator should anticipate an

objective response rate of 5 to 10% due to human error in tumor measurement.”

• Moertel CG, Hanley JA. Cancer 1976;38:388.

• In the early 1980s, the WHO developed recommendations in an attempt to standardize criteria for response assessment

Principles of response evaluation overall cancer burden

quantitative evaluation qualitative evaluation (measurable) (not measurable)target lesions non target lesions

combination estimation of the treatment effect

CR/ PR/ SD/ PD

Specificity of the WHO criteria• Recommends bi-dimentional measurement

– multiply the longest diameter by the greatest perpendicular diameter.

• Response Categories: • two observations not less than 4 weeks apart

– CR = disappearance of all known disease

– PR = 50% decrease in the sum of the products of the perpendicular diameters

– PD = 25% increase in size of lesion or appearance of new lesions.

• Mid 1990s: International working group began to meet to address some shortcomings of WHO. For example:– Complexity (bidimensional measurements)– measuring methods and selection of target

lesions were not clearly described in the WHO guidelines

– New technologies (CT)

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

Key features of the RECIST

• Definitions of minimum size of measurable lesions,

• Instructions on how many lesions to follow • Use of unidimensional, rather than

bidimensional,• Measures for overall evaluation of tumour

burden.

RECIST• 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

RECIST

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)

• Non-target lesions are all other presumed manifestations of the disease• All non-measurable lesions• Measurable lesions that were not chosen as target

lesions• Lesions that may be (but not definitely) metastases

Target Lesions

Definition of Measurable Lesions– 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

collimationex. Slice collimation = 7mm, minimum lesion size = 14mm

Target LesionsDefinition of reproducibly measurable lesions

– Pick lesions with well defined edges or margins– Always measure longest diameter– Measure lesions on same phase or same sequence

(MRI)– Pick lesions that are stable in position, try to avoid

mobile lesions (Avoid mesenteric masses that change in position)

Target Lesionsshould represent distribution of disease

– Pick lesions from disparate areas of the body– For lymphoma choose nodes from different nodal

stations

Target Lesions• Measurable lesions up to a maximum of

– 5 lesions per organ– 10 lesions total

• Sum of longest diameter (SLD) for all target lesions will be calculated at baseline and used as reference to characterize objective tumor response

Quantitative Assessment• The “SLD” is the quantitative assessment• SLD = sum of the longest diameters of target lesions• Strict rules and definitions of:

• Complete response = No measurable disease• Partial Response = Greater than 30% decrease in score• Stable Disease = Between 30% decrease and 20% increase• Progression = Greater than 20% increase in score

• the threshold chosen, a 30% reduction in one dimension, was comparable to the 50% decrease in the sum of the products of the perpendicular diameters used in WHO criteria.

Non – Target Lesions• Non- measurable lesions

Not suitable for accurate repeated measurements

• Ascites • Leptomeningeal disease• Pleural effusions • Inflammatory breast disease• Cystic lesions • Lymphangitis

cutis/pulmonis• Bone lesions • Brain lesions• Irradiated lesions • Ground glass lung lesions

Tumor Response - Target Lesions

• Complete response (CR): Disappearance of all target lesions

• Partial response (PR): > 30% decrease in the SLD

• Stable decrease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD

• Progression (PD): > 20% increase in the SLD

Tumor Response – Non-Target Lesions

• Complete Response (CR): Disappearance of all non-target lesions

• Incomplete Response/Stable Disease (SD): If one or more is Unchanged or Improved and no PD, “not assessed”

• Progression (PD): If at least one “Clearly worse” is present

• Unknown (UN): If “not assessed” or “not imaged” is present

Tumor Response – New Lesions

• New Lesions = Progression (PD)• Any new malignant lesion• Any re-appearing lesion

Tumor Response - Summarized

Target Lesions

Non-target Lesions

New LesionsOverall

Response

CR CR No CR

CR SD 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

WHO RECIST 1.0

Measurable lesion definition

Uni- and bidimensionala

Unidimensional, longest diameter, ≥10 mm (spiral CT); ≥20 mm other

modalities

Disease burden to be assessed at

baselineAll (not specified)

Measurable target lesions up to ten total (five per organ); other lesions

nontarget

Baseline sum

Sum of products of bidimensional diameters or

Sum of linear unidimensional diameters

Sum of longest diameters all measurable lesions

CR Disappearance of all known disease Disappearance of all known disease

PRBidimensional disease, 50%

decrease in sum of products of diametersb

Measurable target lesions, 30% decrease in sum of longest

diameters; all other disease, no evidence of progression

Progression

Measurable disease, ≥25% increase in size of one or more

measurable lesionsc or appearance of new lesions

Measurable disease, 20% increase in sum longest diameters, taking as

reference smallest sum in study; or appearance of new lesions

•33% higher threshold to meet PD

•PR definitions are almost identical

WHO vs RECIST

• Several studies have shown a good concordance between RECIST and WHO for response but less good concordance for time to progression.

• This should be taken into account for planning of future trials

• Since RECIST was published in 2000, the use of unidimensional criteria seems to perform well in solid tumour phase II studies.

However, a number of questions and issues have arisen– whether fewer than 10 lesions can be assessed – whether or how to utilize newer imaging

technologies such as FDG-PET and MRI;– how to handle assessment of lymph nodes;

Revision of the RECIST guidelines includes updates that touch on these points.

Major changes in RECIST 1.1

• Number of target lesions; • Assessment of pathologic lymph nodes; • Clarification of disease progression; • Clarification of unequivocal progression of

non-target lesions; • Inclusion of 18F-FDG PET in the detection of

new lesions

• number of target lesions was reduced – from 5 per organ to 2 per organ and – from a maximum of 10 total to a maximum of 5.

assessment of five lesions per patient did not influence the overall response rate and only minimally affected progression-free survival

• Lymph nodes with a short axis of ≥ 15 mm are considered measurable.– as opposed to the longest axis used for other

target lesions

• PD for target lesions according to RECIST 1.1, – in addition to a 20% increase also consider– a 5-mm absolute increase of the SLD.

small-volume disease

• Clarification of Unequivocal Progression of Nontarget Lesions– SD or PR in target disease + substantial worsening

in nontarget disease = PD– extremely rare

• One of the major changes in RECIST 1.1 is the inclusion of FDG PET

Summary of guideline for including FDG PET

WHO RECIST 1.0 RECIST 1.1

Measurable lesion definition

Uni- and bidimensionalaUnidimensional, longest

diameter, ≥10 mm (spiral CT); ≥20 mm other modalities

Unidimensional, longest diameter tumor lesions ≥10 mm (CT; skin by

calipers); ≥20 mm if CXR

Measurable node definition

Not defined Not defined ≥15 mm short axis

Disease burden to be assessed at

baselineAll (not specified)

Measurable target lesions up to ten total (five per organ); other

lesions nontarget

Measurable target lesions up to five total (two per organ); other

lesions nontarget

Baseline sum

Sum of products of bidimensional diameters or

Sum of linear unidimensional diameters

Sum of longest diameters all measurable lesions

Sum of diameters target lesions, short axis nodes, longest diameter

others

CRDisappearance of all known

diseaseDisappearance of all known

disease

Disappearance of all known disease; malignant nodes must be

<10 mm

PRBidimensional disease, 50%

decrease in sum of products of diametersb

Measurable target lesions, 30% decrease in sum of longest

diameters; all other disease, no evidence of progression

Measurable target lesions, 30% decrease in sum of longest

diameters; all other disease, no evidence of progression

Progression

Measurable disease, ≥25% increase in size of one or more

measurable lesionsc or appearance of new lesions

Measurable disease, 20% increase in sum longest

diameters, taking as reference smallest sum in study; or

appearance of new lesions

20% increase in sum of diameters, with minimum absolute increase of 5 mm, taking as reference smallest

sum in study; or appearance of new lesions

Overall response rate• ORR has been used both in drug development and

in clinical practice to indicate antitumor efficacy of a given agent or regimen.

• According to US FDA ORR = PR + CR– not willing to include SD, as part of the ORR.– as it is often indicative of the underlying disease biology

rather than attributed to the drug’s therapeutic effect• Def. - Portion of patients with a tumor size

reduction of a predefined amount for a minimum time period

• ORR (often) correlates with OS.

clinical benefit rate• To include stable disease – meaningful responses• CBR = CR + PR + SD• Originally delineated to assess the benefit of

gemcitabine in pancreatic cancer. – a composite of measurements of pain, – Karnofsky performance status, and – weight.

• CB required a sustained (4 weeks or longer) improvement in at least one parameter without worsening in any others

Alternate Response Criteria• Not every tumor type has been amenable to

standardized definitions. E.g.– bony disease in prostate cancer, – pleural and peritoneal surface disease in

mesothelioma and ovarian cancer, – and gastrointestinal stroma tumors (GIST),

• often remain the same size as the center of the tumor mass undergoes necrosis

• Different strategies have emerged to quantify these diseases– biomarkers and positron emission tomography

(PET) criteria

Serial Biomarker Levels

• multiple purposes: – for screening, – for early detection of recurrent disease, and – for monitoring response to systemic therapy.

Type Baseline Response Progression

CA 125 in ovarian

cancer (GCIG criteria)

Two pretreatment

samples >2 × ULN

CA 125 decline ≥50%

confirmed at 28 days

2 × nadir OR

2 × ULN if normalized

on therapy

PSA in prostate cancer

(PSA WG 1)a

≥5 ng/mL and

documentation of two

consecutive increases

in PSA over a previous

reference value

PSA decline of 50%

from baseline

(measured twice 3 to 4

weeks apart)

PSA increase by 25%2

above nadir or entry

value (50% increase if

response achieved)

AND

>5 ng/mL, or back to

baseline, whichever is

lower

hCG and AFP in

testicular cancer

Long half-life of

decay(>3.5 days for

hCG, >7 days for AFP)

is indicative of a poor

response

Choi Criteria for GIST

Choi criteria for CT images in GIST ≥10% decrease in tumor size OR

≥15% reduction in tumor density

Type Response

EORTC Criteria for PET

EORTC criteria for

response when using a

PET scan

ROI should be drawn,

SUV calculated

CMR: Complete

resolution of uptake

PMR: SUV reduction

≥25% after more than

one treatment cycle

SMD: <25% increase

and <15% decrease in

SUV

PMD: SUV increase of

>25% in regions

defined on baseline, or

appearance of new

FDG avid lesions

Type Baseline Response Progression

International Working Group Criteria for Lymphoma

• sometimes called the Cheson criteria• CR posttreatment residual mass is allowed if

it becomes PET-negative.• For lymphomas that are not consistently FDG

avid, or FDG avidity is unknown, – CR

• <= 1.5 cm LD if >1.5 cm at baseline, or • <= 1 cm LD if between 1.1 to 1.5 cm at baseline

– PR • >= 50% decrease in SPD at baseline

Waterfall Plots

• WHY? – Arbitrary initial 50% cutoff, and current RECIST threshold of 30% reduction

• Ideally all responses should be confirmed after a period of at least 4 weeks.

• On the left represent patients whose tumors increased, while on the right represent patients whose tumors regressed.

• The vertical red lines at +20% and –30% define the boundaries of stable disease according RECIST

• In cancer drug development – in phase 2 trial

• ORR - indicator of activity, – In phase 3 trials

• other end points, including PFS and time to progression (TTP)

• PFS - from the time of randomization to the time of disease progression or death.

• TTP - the time from randomization to the time of disease progression

• deaths are censored

Progression Free Survival and Time to Progression

• For PFS - death might be an adverse effect of the therapy. 

• For TTP - if a patient dies but the tumor has not meet criteria for progression, one cannot accurately estimate when progression might have occurred, so the data should be censored.

Overall Survival

• Time from randomization to death– gold standard of clinical trial end points

• Unambiguous,• does not suffer from interpretation bias.

• No convincing evidence PFS is a surrogate for OS

• Advantage in PFS or TTP disappears when one looks to OS • PFS is a shorter interval• Patients may receive multiple lines of therapy following

the clinical trial, the results may be confounded by those subsequent therapies.

• Magnitude of the difference does not disappear, only the statistical validity.

• Besides earlier mentioned cancer outcomes (response to treatment, duration of response) second set of outcomes in a clinical trial are patient outcomes.

• i.e.  increase in survival, and the quality of life before and after therapy.

Quality of LifeCore Domains• Psychological

• Social

• Occupational

• Physical

Typical items• Depression/Anxiety/

Adjustment to illness• Personal relationships,

sexual interest, social & leisure activities

• Employment, cope household

• Pain/mobility/sleep/ sexual functioning

Note order of domains; doctors tend to emphasize physical

Quality of Life

• Several instruments to assess QOL have been developed and refined in the past two decades.

• Acc. to earlier studies – QOL = performance status– Related but weak correlations

• Examples that have well-established levels of reliability and validity include – the Functional Living Index-Cancer (FLIC), – the Cancer Rehabilitation Evaluation System Short

Form (CARES-SF), – the Functional Assessment of Cancer Therapy-

General (FACT-G), and – the EORTC Core Quality of Life Questionnaire

(EORTC QLQ-C30).

FLIC (Finkelstein 1988) – • a 22 item instrument • measures quality of life in the following domains: physical/occupational

function, psychological state, sociability and somatic discomfort. • originally proposed as an adjunct measure to cancer clinical trials.

CARES-SF (Schag 1991) – • 59 item scale • measures rehabilitation and quality of life in patients with cancer. • This has been modified to the HIV Overview of Problems Evaluation

Systems (HOPES, Schag 1992) EORTC QOL-30 (Aaronson 1993) –

• composed of modules to assess quality of life for specific cancers in clinical trials.

• The current instrument is 30 items with physical function, role function, cognitive function, emotional function, social function, symptoms, and financial impact.

FACT-G (Cella 1993) –• a 33 item scale • developed to measure quality of life in patients undergoing cancer

treatment.

• Thank u…..