Everything about response evaluation in solid tumours RECIST and WHO

1. Clinical response assessment in
solid tumours
Dr Pallavi Kalbande
Assistant Professor

2. Need of response evaluation
• Clinical evaluation of cancer therapeutics
• Both tumour shrinkage (objective response) and time
to the development of disease progression are
important endpoints in cancer clinical trials

3. 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

4. • Early attempts were made in the early 1960s
• 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.

5. Measurement tool
• 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

6. • Moertel and Hanley recommended:
• 50% reduction criterion should be
applied in clinical settings
• Investigator should anticipate an objective
response rate of 5 to 10% due to human
error in tumor measurement
Moertel CG,Hanley JA.Cancer1976;38:388

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

8. Specificity oftheWHO criteria
• Recommends bi-dimentional measurement
multiply the longest diameter by the greatest
perpendicular diameter
• Two observations not less than 4 weeks apart

10. Principlesof responseevaluation
overall cancerburden
Quantitative evaluation
(measurable)
Target lesions
Qualitative evaluation
(not measurable)
NonTarget lesions
combination
estimation of the treatmenteffect
CR/PR/SD/ PD

11. WHO DEFINITIONS
• Disappearance of all known disease
Complete
response
• 50% decrease in the products of the
perpendicular diameters
Partial response
• 25% increase in size of lesion or
appearance of new lesions
Progressive
disease
25% of increase or <50% of reduction
Stable disease

12. • Complexity (bidimensional measurements)
– measuring methods and selection of target
lesions were not clearly described in theWHO
guidelines
New technologies (CT)
Shortcomings of WHO

13. Response evaluation criteria in solid tumors:
“RECIST” working group
• 1994 international task force
• (EORTC)
• National Cancer Institute (NCI) of the U.S.
• National Cancer Institute of Canada Clinical Trials Group
• Recommendation to simplify response evaluation
• 1999: Criteria was publicly presented/accepted the American
Society for Clinical Oncology meeting
• 2000: Published in Journal of the National Cancer Institute

14. Key featuresofthe 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

15. Target lesions
• Easily (and reproducibly) measurable
• Representative of the disease (clearly
metastasis)
• Representative of distribution (choose
measurable lesions from all involved organs)

16. • All non-measurablelesions
• Measurable lesions that were not chosen as
target lesions
• Lesionsthat maybe (but not definitely)
metastases
Non-target lesions

17. 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
eg. Slice collimation = 15mm, minimum lesion size =
30mm
Conventional CT or MRI (non-spiral – 2 cm)

18. 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
Spiral CT-1cm
Measurable lesions

20. Reproducible 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)

22. Nooflesions
• maximumof
5 lesions per organ 10 lesions total
measure longest diameter
Sumof longest diameter (SLD)
All target lesions will be calculated at
baseline and used asreference to
characterize objective tumor response

23. Quantitative assessment
• No measurable disease
Complete
response
• Greater than 30%
decrease in score
Partial Response
• Not stable or progressive
disease
Stable Disease
• Greater than 20%increase
in score
Progression

25. Water fallplots
• WHY ? – current RECIST threshold of
30%reduction
• Ideally all responses should be confirmedafter
aperiod of at least 4weeks.

26. • Onthe left represent patients whose tumors
increased, while on the right represent patients
whose tumors regressed.
• Thevertical red lines at +20%and –30%definethe
boundaries of stable disease accordingRECIST

27. Non–target lesions
• Non- measurable lesions
Not suitable for accurate
repeated measurements
• Ascites
• Pleural effusions
• Cysticlesions
• Bone lesions
• Irradiated lesions
• Leptomeningeal disease
• Inflammatory breastdisease
• Lymphangitis cutis/pulmonis
• Brain lesions
• Ground glasslung lesions

28. Tumor response – non-target lesions
• All non-target lesions gone
• Tumor markers to normal levels
Complete
Response
Stable Disease • Persistence of >1 non-target lesion
• Tumor marker level elevated
Progression • Enlargement of non-target lesions

29. • Hypervascular rim, this is included in measuring the
longest diameter, because it represent viable tumor tissue

30. • malignant pleural mesothelioma
• Not the longest diameter, but the tumour thickness
perpendicular to the chest wall is used.

31. • During follow-up bone metastases quite often change in
appearance while the size remains the same
• Generally considered non-measurable lesions
• Only lytic or mixed lytic-blastic bone metastases with
identifiable soft tissue component are considered as
measurable lesions

32. TUMOR RESPONSE - SUMMARIZED
Target
Lesions
Non-target
Lesions
New Lesions
Overall
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

33. 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
baseline
All (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
PR
Bidimensional 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

34. Un-answered questions
• Whetherfewerthan10lesionscanbeassessed?
• Whetherorhowtoutilizenewerimaging
technologiessuchasFDG-PETandMRI ?
• Howtohandleassessmentoflymphnodes ?

35. MajorchangesinRECIST 1.1(jan2009)
• 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

36. • Number of target lesions
• Lymph nodes with a
are considered measurable
– as opposed to the longest axis used for
other target lesions
5 per organ 2 per organ
maximum of 10 maximum of 5

37. • PD - 20% increase
• 5-mm absolute increase of the SLD
• Clarification of Unequivocal
Progression of Nontarget Lesions
SD or PR in target disease + substantial
worsening in nontarget disease = PD
RECIST 1.1
• One of the major changes in RECIST 1.1 is
the inclusion of FDG -PET

38. • E.g. Carcinoma of the appendix with liver, lymphogenic and
peritoneal metastases.

39. Summary of guideline for including FDG PET

40. WHO RECIST 1.0 RECIST 1.1
Measurable
lesion definition
Uni- and bidimensionala
Unidimensional, 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 baseline
All (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
CR
Disappearance of all known
disease
Disappearance of all known
disease
Disappearance of all known
disease; malignant nodes must
be <10 mm
PR
Bidimensional 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

41. Overall response rate
• 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
• ORR (often) correlates with OS

42. Alternate response criteria
• Not every tumor type hasbeen amenableto
standardized definitions
– bony disease in prostate cancer
– pleural and peritoneal surface
disease in mesothelioma and
ovarian cancer
– gastrointestinal stroma tumors (GIST)

43. • Often remain the same size as the
center of the tumor mass undergoes
necrosis
• Different strategies have emerged to
quantify these diseases
– Biomarkers
– positron emission tomography (PET)
criteria

44. Serial biomarker levels
• multiple purposes:
– for screening
– for early detection of recurrent disease
– for monitoring response to systemic
therapy

45. 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 × nadirOR
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

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

47. 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

48. International workinggroupcriteria
for lymphoma
• Also known as Cheson criteria
• Complete Response
post treatment residual mass is allowed if
it becomes PET-negative

49. • For lymphomas that are not consistently
FDG avid or FDG avidity is unknown
CR
• 1.5 cm LD if >1.5 cm at baseline
• 1 cm LD if between 1.1 to 1.5 cm at baseline
PR
• 50% decrease in SLD at baseline
International workinggroupcriteria
for lymphoma

50. Response assessment in lymphomas

51. Summary
• RESIST 1.1 for solid tumours
• Target lesion
• Measurable lesion longest diameter 1cm on CT
scan
• For lymphnodes shortest diameter of 1.5 cm
• Non target lesion = non measurable lesion
• 2per organ
• maximum 5 in total
• Sum of longest diameter (SLD)

52. • CR – no measurable disease
• PR – 30% or more decrease
• PD - 20% or more increase
• SD – not PD or PR
CHOI Criteria for GIST
Deauville score for Lymphoma

53. Radiologyassistant.Nl/more/recist-1-1/recist-1-1
Further reading