general oncology from devita presentation

1. ASSESSMENT OF CLINICAL
RESPONSE

2. Introduction:
 Assessment of the change in tumor burden is an
important factor of clinical evaluation of cancer
therapeutics.
 Tumor regression as the end point for phase II trials
screening new agents for evidence of tumor
shrinkage is supported by years of evidence
suggesting that, for many solid tumors, agents
which produces regressions in a proportion of
patients have a reasonable chance of subsequently
demonstrating an improvement in OS in phase III
studies.
 Both tumor shrinkage (objective response) and
disease progression are useful end points in clinical
trials.

3. Introduction contd…….
• Tumor shrinkage and time to disease progression are useful only if
based on widely accepted and readily applied standard criteria
based on anatomical burden.
• In 1981 WHO first published tumor response criteria ,mainly for
use in trials where tumor response was the primary end point.
• WHO criteria included tumor burden by summing up the product
of bi-dimensional lesions measurements and determined response
assessment.
• Cooperative groups and pharmaceuticals often modified WHO
criteria and this led to confusion in interpretation of data of trials.
• In response to these problems in the year 2000 RECIST criteria
were published .

4. Response Evaluation Criteria in
Solid Tumors
Revised RECIST Guideline Version 1.1

5. Purpose of this Guideline :
 Standard approach to solid tumor measurement and
definition for objective assessment of change in tumor
size for use in adult and pediatric cancer clinical trials.
 Guidelines may be applied in malignant brain tumor
studies. Guidelines are not intended for use for studies of
malignant lymphomas.
 RECIST guideline do not intend to play a role in decision
making in daily oncology clinical practice.
 In routine oncology practice decision of continued
therapy is based on objective and symptomatic criteria.

6. Measurability of tumor at baseline :
A. Measurable disease – Tumor and Node
Tumor Lesion :
Must be accurately measured in at least one
dimension ( longest diameter in the plane of
measurement is to be recorded ) with a minimum size
of :
— 10 mm by CT Scan.
— 10 mm caliper measurement by clinical exam
(lesions which cannot be measured by caliper accurately
should be recorded as non-measurable)
— 20 mm by Chest X-ray.

7. Measurable Disease :
Malignant Nodal Lesion :
— To be considered pathologically enlarged
and measurable, a lymph node must be ≥
15mm in short axis when assessed by CT
scan.
— At baseline and in follow up only the short
axis will be measured and followed.

8. Non-measurable Lesions:
 All other lesions including small lesions (longest diameter
<10mm or pathological lymph nodes with ≥10 to <15mm
short axis) as well as truly non-measurable lesions like :
— Leptomeningeal disease.
— Ascites
— Pleural effusion
— Pericardial effusion
— Inflammatory breast disease.
— Lymphangitic carcinomatosis skin/lung.
— Abdominal masses identified by clinical examination
that is not measurable by reproducible imaging
study.

9. Special consideration regarding
lesion measurability
A. Bone Lesion :
— Bone Scan, PET Scan or plain films are not
considered adequate imaging techniques to measure bone
lesion.
— Lytic bone lesions or mixed lytic blastic lesions,
with identifiable soft tissue components, that can be
evaluated by cross sectional imaging techniques such as
CT or MRI can be considered as measurable lesions if the
soft tissue component meet the definition of
measurability.
— Blastic bone lesions are non-measurable.

10. B. Cystic Lesion :
— Cystic lesions thought to represent cystic
metastases can be considered as measurable
lesion, if they meet the definition of measurability.
C. Lesion with prior local treatment :
— Tumor lesion situated in a previously irradiated
area, or in an area subjected to other loco-regional
therapy, are usually not considered measurable
unless there has been demonstrated progression in
the lesion.

11. Specifications by methods of
measurements
 Measurement of Lesion :
— All measurement should be recorded in metric
notation, using calipers if clinically assessed.
— All baseline evaluations should be performed as
close possible to the treatment start and never than
4 weeks before the beginning of the treatment.

12. . Method of Assessment
The same method of assessment and the same technique
should be used to characterize each identified and reported
lesion at baseline and during follow up :
A. Clinical Lesion :
— Clinical lesion will only be considered measurable
when they are superficial and ≥ 10mm diameter
as assessed using calipers eg. Skin nodule.
— When lesion can be evaluated by both clinical
and imaging, imaging evaluation should be
undertaken since it is more objective and may be
reviewed at the end of the study.

13. B. Chest X-ray :
— Chest CT is preferred over chest X-ray, particularly
when progression is an important endpoint (CT is more
sensitive in identifying new lesions then xray)
— Lesion on Chest X-ray may be considered measurable if
they are clearly defined and surrounded by aerated lung.
C. CT / MRI :
New RECIST guideline has defined measurability of lesion on CT
scan based on the assumption that CT slice thickness is 5mm
or less.
— If CT scan have slice thickness greater >5mm the
minimum size for a measurable lesion should be twice the
slice thickness.
Method of Assessment contd……..

14. D. Ultrasonography :
— Not useful in assessment of lesion because they are
operator dependent.
— A new lesion on USG should be reconfirmed on
CT/MRI
E. Endoscopy/Laparoscopy :
— Not advised.
— They can be useful to confirm complete pathology
response when biopsies are obtained.
Method of Assessment contd……..

15. F. Tumor Markers :
— Alone can not be used to assess objective tumor response.
— If marker are initially above the upper normal limits,
however they must normalize for a patient to be considered
in complete response.
G. Cytology/Histology :
— These techniques can be used to differentiate between
PR and CR in rare cases if required by protocol, eg. Residual
lesion in tumor types such as germ cell tumor, where known
residual benign tumors can remain.
Method of Assessment contd……..

16. Tumor Response Evaluation

17. Baseline documentation of target and
non-target lesions
 Measurable disease is defined by the presence of at least one
measurable lesion.
 When > 1 measurable lesion is present at baseline all lesion up to a
maximum of 5 lesion total (& a max. of 2 lesions per organ)
representative of all involved organs should be identified as target
lesions and are recorded and measured at baseline.
 For nodal involvement short axis should be ≥ 15mm by CT scan. All
other node >10mm but <15mm should be considered as non-target,
LN short axis <10mm are considered non pathological and should not
be recorded.
 A sum of the diameters for all targets lesions will be calculated
& reported as the baseline sum diameter . If LNs are to be
included in the sum ,then only the short axis is added in the
sum.

18. Response Criteria :
CR : Disappearance of all target lesion : Any pathological
lymph node (whether target or non target) must have
reduction in short axis to <10mm.
PR : At least a 30% decrease in the sum of diameters of
target lesions taking as reference the baseline sum
diameters.
PD : 20% increases in the sum of diameter of target
lesion taking as reference the smallest sum on study.
Appearance of one or more new lesion is also
considered progression.
SD : Neither sufficient shrinkage to qualify for PR nor
sufficient increase to qualify of PD.

19. Evaluation of non-target lesion :
CR : Disappearance of all non target lesion and
normalization of tumor markers level. All lymph node
must be non pathological in size (<10mm short axis)
Non CR/Non PD : Persistence of one or more non target
lesion and/or maintenance of tumor marker level above
the normal limits.
PD : Unequivocal progression of exiting non target lesions
or appearance of one or more new lesion.

20. New lesion on basis of FDG-PET imaging can be identified
according to following algorithm

21. Evaluation of best overall response :
 The best overall response is the best response recorded
from the start of the study treatment until the end of
treatment taking into account any requirement for
confirmation.
 Best overall response assignment will depend on the
finding of both target and non target disease and will also
take into extent the appearance of new lesion.
 It is assumed that each protocol should specify time point
when response assessment occur.

22. Time point response : patients with target (+/– non-target) disease.
Target Lesions Non-target Lesions New
Lesions
Overall
Response
CR CR No CR
CR Non-CR/Non-PD No PR
CR Not evaluated No PR
PR Non-PD or not all evaluated No PR
SD Non-PD or Not all evaluated No SD
Not all evaluated Non-PD No NE
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
CR = complete response, PR = partial response, SD = Stable disease,
PD = progressive disease, and NE = in evaluable.

23. Time point response : patients with non-target disease only
Non-target Lesions New Lesions Overall Response
CR No CR
Non-CR/Non-PD No Non-CR/Non-PD
Not all evaluated No NE
Unequivocal PD Yes or No PD
Any Yes PD
CR = complete response, PD = Progressive Disease, and NE =
Inevaluable.
A ‘Non-CR/Non-PD’ is preferred over ‘stable disease’ for non-target
disease since SD is increasingly used as endpoint for assessment of
efficacy in some trials so to assign this category when no lesions can be
measured is not advised.

24. Best overall response when confirmation of CR and PR required
Overall response
first time point
Overall response Subsequent
time point
BEST overall response
CR CR CR
CR PR SD, PD or PR2
CR SD SD provide minimum criteria for SD
duration met, otherwise, PD
CR PD SD provide minimum criteria for SD
duration met, otherwise, PD
CR NE SD provide minimum criteria for SD
duration met, otherwise, NE
PR CR PR
PR PR PR
PR SD SD
PR PD SD provide minimum criteria for SD
duration met, otherwise, PD
PR NE SD provide minimum criteria for SD
duration met, otherwise, PD
NE NE NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whatever
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest lesions were likely still
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR
and the best response if PR.

27. Future Functions :
 A key question considered by the RECIST working group
in developing RECIST 1.1 was whether it was appropriate
to move from one time unidimensional assessment of
tumor burden to either volumetric anatomical
assessment or the functional assessment with PET-
CT/MRI.
 Presently there is not sufficient standardization or
evidence to abandon anatomical assessment of tumor
burden.

28. ALTERNATE RESPOSNSE CRITERIA
• International Working Group Criteria for Lymphoma
• Severity-Weighted Assessment Tool Score in Cutaneous T-Cell
Lymphoma
• Pathologic Complete Response in Breast Cancer
• Computed Tomography-Based Tumor Density
• FDG-PET : EORTC Criteria
PERCIST Criteria
• Serum Biomarkers of Response

29. International Working Group Criteria for Lymphoma
(Cheson Criteria)
• Guidelines incorporated 18FDG-PET assessments in metabolically active
lymphomas.
• CR : Complete disappearance of detectable disease
Or posttreatment residual mass is permitted if it is
negative on FDG-PET and was positive at baseline.
• For lymphomas that are not consistently FDG avid, or if FDG avidity is
unknown,
 CR : Nodes >1.5 cm before therapy regress to <1.5 cm
Nodes 1.1 to 1.5 cm in long axis and >1.0 cm in the
short axis shrink to ≤1.0 cm in short axis
 PR: ≥ 50% decrease in the sum of the product of the diameters

30. Severity-Weighted Assessment Tool Score in Cutaneous
T-Cell Lymphoma (SWAT)
• SWAT assigns a factor for skin lesion severity—patch, plaque,
or tumor—multiplies this factor by the percent of skin involved
with each lesion type and then adds these together.
• This complex system formed the basis of the FDA approval of
vorinostat for CTCL.

31. Pathologic Complete Response in Breast Cancer
• One unique response endpoint is the assessment of breast cancer
treated in the neoadjuvant setting
• Pathologic complete response (pCR): Absence of cancer cells
in resected breast tissue
• The rate of pCR has been proposed as a surrogate endpoint for
EFS or OS to support approval of new agents or combinations
of agents tested in clinical trials

32. Computed Tomography-Based Tumor Density
• Choi criteria
• Advocates assessing tumor response in GIST, RCC, or HCC
based on density on computed tomography (CT) scans

33. FDG PET
• FDG-PET has become part of standardized response criteria for clinical
trials only in lymphoma
• In solid tumors, FDG-PET can aid in the detection of new or recurrent
sites of disease, and can be used as an adjunct during assessments for
disease progression when using RECIST criteria.
• FDG uptake is a powerful diagnostic tool & its uptake reflects a tumor’s
metabolic activity
• Limitations: Some tumors have variable FDG avidity; differences can
occur due to
 variations in patient activity
 carbohydrate intake, blood glucose, and timing;
 several benign sources of uptake, including inflammatory and
postsurgical sites

34. •FDG PET CRITERIA
SUL, SUV normalized to lean body mass.

35. Serum Biomarkers of Response
• Circulating protein biomarkers have been identified and
studied for several decades for screening, early detection of
recurrent disease, determining prognosis, selecting therapy,
and monitoring response to therapy.

36. DETERMINING OUTCOMES
• The response measures described previously represent different
approaches to quantitate tumor burden.
• The FDA conveys full approval to new agents based on true
clinical benefit (i.e., an improvement in a survival endpoint or
symptom relief)
• Surrogates for clinical benefit, such as response rate, may
support either regular approval or accelerated approval,
depending on the setting

37. • Endpoints Based on Tumor Assessments
Disease Free Survival (DFS)
Objective response rate (ORR)
Progression free survival (PFS)
Time to Progression (TTP)
Time-to-treatment failure (TTF)
• Endpoints Involving Symptom Assessment
• Quality of life

38. Overall Survival Rate, Duration of response & Stable Disease
• Overall response rate (ORR) is the proportion of patients with a
tumor size reduction of a predefined amount for a minimum
time period.
• FDA defined ORR as : PR + CR
Stable Disease (SD), defined as shrinkage that qualifies as
neither response nor progression are not included as part of the
ORR,
As it is often indicative of the underlying disease biology rather
than a drug’s therapeutic effect
• ORR often correlates with OS

39. • CBR (Clinical benefit rate) , which includes CR + PR + SD and
which is a misuse of the term clinical benefit because neither CR, PR,
or SD are objective tumor findings that address the true clinical
benefit of a therapy.
• SD should not be used as a response endpoint
• A better approach is to use nondichotomized response assessments,
such as the waterfall plot

40. Waterfall Plot
• The arbitrary nature of the 50% cutoff set by Moertel and Hanley and its
evolution to the current RECIST threshold of 30% reduction in the size of the
maximum diameter raises valid queries as to why 30% is valuable and not 29%
or 25%.
• Waterfall plot demonstrating for each patient the maximum benefit obtained with
the study therapy.
• Left represent patients whose tumors increased, and right patients whose tumors
regressed.
• The vertical red lines at +20% and -30% define the boundaries of stable disease
according to RECIST.

41. • Ideally, all responses should be confirmed after a period of at
least 4 weeks
• In cancer drug development,
In phase II trials, ORR assessed as an indicator of activity,
Randomized phase III trials rely on other endpoints such as
progression-free survival (PFS) and time to progression
(TTP)

42. Progression-Free Survival, Time to
Progression, and Time to Treatment Failure
• PFS is defined from the time of randomization to the time of
disease progression or death.
• TTP is defined as the time from randomization to the time of
disease progression. (deaths are censored)
• Those who favor TTP argue that if a patient dies without their
tumor meeting criteria for progression, one cannot accurately
estimate when progression might have occurred, so the data
should be censored.
• Those who favor PFS argue that, in some cases, death might be
an adverse effect of the therapy.

43. • In the majority of tumors there is no convincing evidence PFS is
a surrogate for OS, and in those where there is some evidence,
its value is arguable

44. • Time to treatment failure (TTF) defined as a composite
endpoint measuring time from randomization to
discontinuation of treatment for any reason, including disease
progression, treatment toxicity, and death.
• The FDA has not recommended TTF as a regulatory endpoint
for drug approval.

45. Overall Survival :Gold standard of clinical trial end points
• OS defined as the time from randomization to death
• When evaluating a randomized controlled trial, it is important that the OS as well as
the PFS analyses are always by intention to treat (ITT).
• In an ITT analysis, often described as once randomized, always analyzed & avoids
bias introduced by omitting dropouts & noncompliant patients that can negate
randomization & overestimate clinical effectiveness.

46. Kaplan Meier Plots
• The Kaplan-Meier survival curve is defined as the probability of
surviving in a given length of time while considering time in
many small intervals.
• In discrete time intervals, the number of patients in each group
who are progression free and alive (PFS analysis) or alive (OS
analysis) at the end of the interval are counted and divided by
the total number of patients in that group at the beginning of the
time interval.
• One excludes from this calculation patients censored for a
reason other than progressive disease or death during the same
interval.

47. • This has the advantage that it allows one to include censored
patients in estimates of the probability of PFS or OS up to the
point when they were censored (i.e., they are excluded only
beyond the point of censoring).
• In constructing the Kaplan–Meier plot, probabilities are
calculated for each interval of time.

48. Hazard Ratio
• Hazard ratio is a ratio of the hazard rates.
• The hazard rate quantifies the likelihood that a patient will experience
a hazardous event or a hazard during a defined interval of
observation,
• Expressed as a rate or percent
• Lower the hazard ratio, the better the experimental therapy.
• To determine whether the hazard ratio has statistical significance, one
can use a log-rank test .
• In many cases cox proportional hazard model is used.

49. Forest Plot
• A forest plot is a graphical representation of a meta-analysis
• The information one seeks from a Forest plot is whether the effect
size for different subgroups varies significantly from the main
effect, which is determined by a test for heterogeneity.

50. Quality of Life end point
• Global health-related quality of life (HRQL) have not served as
primary efficacy endpoints in oncology drug approvals
• They are usually patient reported outcome measures
• For QOL to be used as primary endpoints to support cancer drug
approval, the FDA should be able to distinguish between
improvement in tumor symptoms and lack of drug toxicity
• An apparent effectiveness advantage based on a global QoL
instrument can simply indicate less toxicity rather than
effectiveness

51. Thank You