1. CLINICAL RESPONSE
ASSESSMENT
Dr. Varun Goel
Medical oncologist
Rajiv gandhi cancer institute

2. 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

3. 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.

4. • 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

5. • 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.

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

7. 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

8. 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.

9. • 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)

10. 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

11. 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.

12. 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

13. 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

14. 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
collimation
ex. 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

15. Target Lesions
Definition 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)

16. Target Lesions
should represent distribution of disease
– Pick lesions from disparate areas of the body
– For lymphoma choose nodes from different nodal
stations

17. 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

18. 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.

19. 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

20. 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

21. 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

22. Tumor Response – New Lesions
• New Lesions = Progression (PD)
• Any new malignant lesion
• Any re-appearing lesion

23. Tumor Response - Summarized
Target Non-target Overall
New Lesions
Lesions Lesions 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

24. WHO RECIST 1.0
Unidimensional, longest diameter,
Measurable lesion
Uni- and bidimensionala ≥10 mm (spiral CT); ≥20 mm other
definition
modalities
Disease burden to Measurable target lesions up to
be assessed at All (not specified) ten total (five per organ); other
baseline lesions nontarget
Sum of products of
bidimensional diameters or Sum of longest diameters all
Baseline sum
Sum of linear unidimensional measurable lesions
diameters
Disappearance of all known Disappearance of all known
CR
disease disease
Measurable target lesions, 30%
Bidimensional disease, 50%
decrease in sum of longest
PR decrease in sum of products of
diameters; all other disease, no
diametersb
evidence of progression
Measurable disease, 20% increase
Measurable disease, ≥25%
in sum longest diameters, taking
increase in size of one or more
Progression as reference smallest sum in
measurable lesionsc or
study; or appearance of new
appearance of new lesions
lesions

25. WHO vs RECIST
•33% higher
threshold to meet PD
•PR definitions are
almost identical

26. • 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

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

28. 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.

29. 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

30. • 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

31. • 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

32. • One of the major changes in RECIST 1.1 is the
inclusion of FDG PET
Summary of guideline for including FDG PET

33. WHO RECIST 1.0 RECIST 1.1
Unidimensional, longest
Unidimensional, longest
Measurable diameter tumor lesions ≥10 mm
Uni- and bidimensionala diameter, ≥10 mm (spiral CT);
lesion definition (CT; skin by calipers); ≥20 mm if
≥20 mm other modalities
CXR
Measurable node
Not defined Not defined ≥15 mm short axis
definition
Disease burden Measurable target lesions up Measurable target lesions up to
to be assessed All (not specified) to ten total (five per organ); five total (two per organ); other
at baseline other lesions nontarget lesions nontarget
Sum of products of
Sum of diameters target lesions,
bidimensional diameters or Sum of longest diameters all
Baseline sum short axis nodes, longest
Sum of linear unidimensional measurable lesions
diameter others
diameters
Disappearance of all known
Disappearance of all known Disappearance of all known
CR disease; malignant nodes must
disease disease
be <10 mm
Measurable target lesions,
Measurable target lesions, 30%
Bidimensional disease, 50% 30% decrease in sum of
decrease in sum of longest
PR decrease in sum of products longest diameters; all other
diameters; all other disease, no
of diametersb disease, no evidence of
evidence of progression
progression
20% increase in sum of
Measurable disease, 20%
Measurable disease, ≥25% diameters, with minimum
increase in sum longest
increase in size of one or absolute increase of 5 mm,
Progression diameters, taking as reference
more measurable lesionsc or taking as reference smallest
smallest sum in study; or
appearance of new lesions sum in study; or appearance of
appearance of new lesions
new lesions

34. 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.

35. 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

36. 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

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

38. Type Baseline Response Progression
CA 125 in ovarian Two pretreatment CA 125 decline ≥50% 2 × nadir OR
cancer (GCIG criteria) samples >2 × ULN confirmed at 28 days 2 × ULN if normalized
on therapy
PSA in prostate cancer ≥5 ng/mL and PSA decline of 50% PSA increase by 25%2
(PSA WG 1)a documentation of two from baseline above nadir or entry
consecutive increases (measured twice 3 to 4 value (50% increase if
in PSA over a previous weeks apart) response achieved)
reference value AND
>5 ng/mL, or back to
baseline, whichever is
lower
hCG and AFP in Long half-life of
testicular cancer decay(>3.5 days for
hCG, >7 days for AFP)
is indicative of a poor

39. Type Response
Choi Criteria for GIST
Choi criteria for CT images in ≥10% decrease in tumor size OR
GIST ≥15% reduction in tumor density

40. Type Baseline Response Progression
EORTC Criteria for PET
EORTC criteria for ROI should be drawn, CMR: Complete PMD: SUV increase of
response when using a SUV calculated resolution of uptake >25% in regions
PET scan PMR: SUV reduction defined on baseline, or
≥25% after more than appearance of new
one treatment cycle FDG avid lesions
SMD: <25% increase
and <15% decrease in
SUV

41. 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

42. 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.

43. • 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

44. • 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)

45. Progression Free Survival and Time to
Progression
• 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

46. • 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.

47. Overall Survival
• Time from randomization to death
– gold standard of clinical trial end points
• Unambiguous,
• does not suffer from interpretation bias.

48. • 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.

50. • 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.

51. Quality of Life
Core Domains Typical items
• Psychological • Depression/Anxiety/
Adjustment to illness
• Social • Personal
relationships, sexual
interest, social &
leisure activities
• Occupational
• Employment, cope
household
• Physical • Pain/mobility/sleep/
sexual functioning
Note order of domains; doctors tend to emphasize physical

52. 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

53. • 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).

54.  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.

55. • Thank u…..