Title: The Need for Quantitative Imaging in Oncology
1The Need for Quantitative Imaging in Oncology
- Richard L. Schilsky, M.D.
- Professor of Medicine,
- Associate Dean for Clinical Research, University
of Chicago - Chairman, Cancer and Leukemia Group B
2The Role of Imaging in Oncology
- Detection
- Staging (assess prognosis)
- Treatment planning
- Assess response/progression (assess benefit)
- Monitor recurrence
3The Role of Imaging in Oncology
- Is a tumor present?
- Where is it?
- How big is it?
- How deep is it?
- What is it near?
- Is it growing/shrinking/spreading?
4Clinical Practice vs. Clinical Research
- Mostly a matter of precision
- Practice setting information that impacts
clinical management of an individual, e.g., when
to start/change/stop treatment assess extent of
disease and cause of symptoms - Research setting information that assesses an
intervention in a population, e.g., precise
staging accurate tumor dimensions assessment of
response/progression
5Clinical Benefit
- Improved survival compared to no treatment or to
a known effective therapy - Non-inferiority to a known effective therapy
- Improvement in TTP compared to known effective
treatment coupled with symptomatic improvement
6Activity vs. Benefit
- Dont confuse activity with benefit
- Activity is the effect on a surrogate or clinical
endpoint of administering the drug - Efficacy is the overall benefit (adjusted for
risk) of prescribing the drug (for a specific
indication) - Activity is necessary but not sufficient for
efficacy
7Survival
- Unambiguous endpoint that is not subject to
investigator interpretation or bias from
unblinded studies - Assessed easily, frequently
- No tumor measurements required!!
8Response Rate
- Treatment is entirely responsible for tumor
reduction unlikely due to natural history - Endpoint reached quickly
- Response criteria arbitrary
- CR and duration of response important
- Classical endpoint to screen for activity
accepted surrogate for clinical benefit
9Response Criteria
- WHO PR is gt 50 decrease in the sum of the
product of the perpendicular diameters of
measurable lesions - RECIST PR is gt 30 decrease in the baseline sum
of the longest diameters of target lesions - Each represents a 65 decrease in volume
- Confirmation 4 weeks later required
10Criteria for Progression
- WHO PD is gt 25 increase in the sum of the
product of the perpendicular diameters of
measurable lesions (40 increase in volume) - RECIST PD is gt 20 in the sum of the longest
diameters of target lesions (73 increase in
volume) - RECIST is biased toward stable disease
11What is Measurable?
- Lesion measured in one dimension as gt 20 mm with
conventional techniques or gt 10 mm with spiral CT
(5 mm reconstruction) - All measurable lesions up to max. of 10 are
considered target lesions - All of this is completely arbitrary and
observer/technology-dependent!
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19You have to see it before you can measure it!
20CT helps in the removal of most structure noise
21case ctn048, ctn008 - section 17
Vast Amount of Data
From S. Armato
22Measurable?
Erasmus, J. J. et al. J Clin Oncol 212574-2582
2003
23Measurable?
Erasmus, J. J. et al. J Clin Oncol 212574-2582
2003
24Is RR Predictive of Benefit?
- For hematologic malignancies, CR generally
associated with symptomatic improvement, reduced
transfusion requirement, reduced infection rates - Buyse et. al. (Lancet, 2000) meta analysis of 25
CRC trials with fluoropyrimidines tumor
response a highly significant predictor of
survival, independent of PS
25Is RR Predictive of Benefit?
- Chen et. al. (JNCI, 2000) phase II response
rates in patients with extensive SCLC did not
correlate with median survival in phase III
trials of same regimen - Irinotecan (15) docetaxel (38) capecitabine
(18.5) oxaliplatin (9) all improved survival
in randomized trials - In many other studies, a significant improvement
in RR does not result in improved survival
26Is RR Predictive of Benefit?
- RR is reasonably likely to predict clinical
benefit, at least for certain diseases and
certain drugs - Is there a minimum RR predictive of benefit and
how is it best measured? - Is another surrogate predictive for drugs that do
not cause regression?
27BAY 43-9006 RDTTrial Schema
gt 25 Tumorshrinkage
-25 to 25Tumor stabilization
BAY 43-9006 12 week run-in
gt 25Tumor growth
28BAY 43-9006 RDT Design
- All patients initially receive BAY 43-9006
- Enrichment of randomized population for endpoint
of interest - Distinguishes antiproliferative activity of drug
vs. the natural history of disease - Requires less overall sample size compared to RCT
- Design controls, in part, for heterogeneity in
enrolled patients, as rapid progressors drop out
29BAY 43-9006 (sorafenib) Study RCC Bidimensional
Tumor Measurements at Week 12Change from
Baseline in Target Lesions (n89)
gt 25 Growthlt 25 to gt-25 Changegt-25 to -49
Shrinkagegt -50 Shrinkage
7
45 24
13
Change in Tumor Measurement
Number of Patients
Investigator assessed 7 of 45 patients
not randomized
30Response vs. Stable Disease
- The distinction between minor responses and
partial responses is based on arbitrary criteria - The patient doesnt care whether the tumor shrank
by 40 (bidimensional) or 60 - So why should we?
31BAY 43-9006 (sorafenib) Study Progression-Free
Survival in RCC Patients Continuing Beyond
Initial 12 Weeks
Open Label BAY (n37)Median 48 weeks(88
progression free at 24 weeks)
Randomized (n38) Median 23 weeks(41
progression free at 24 weeks)
12 Weeks 24 Weeks
Responders at 12 week assessment with gt25
tumor shrinkage
32Time to Progression
- Includes all patients in analysis
- Endpoint sooner than survival no crossover
effect - Definition of progression
- -death due to cancer
- -new lesions
- -increase in size of existing lesions (?)
- -?increase in tumor metabolism
- -? increase in plasma level of tumor marker
- -? decline in PS or increase in symptoms
33Time to Progression Measurement Considerations
- Minimum interval between tumor assessments should
be less than the expected treatment effect size
- Tumor assessment frequency should be the same
across study arms even when cycles are of
different lengths
34Time to Progression
- Precision depends on identification of all
lesions at baseline and on frequency of
evaluation - Always an estimate since actual progression
occurs between observations - Requires control for rate of progression in
absence of treatment effect - Unblinded studies subject to ascertainment bias
35TTP Better Categorizes Tumor Control Than
Response Rate
36How Things Are Changing
- Non invasive staging
- Imaging targets for dose finding
- Neoadjuvant chemotherapy to assess response
- Early response assessment
- Greater reliance on time to progression
37PET-CT Staging of Esophageal Cancer
Enzinger, P. C. et al. N Engl J Med
20033492241-2252
38PET-CT Staging of NSCLC
Lardinois, D. et al. N Engl J Med
20033482500-2507
39DCE MRI in CRC Patient Treated with PTK 787
Baseline Day 2
Ki dropped from 100 baseline to 31 on day
2 34 at end cycle 1 15 at
end cycle 2
Thomas et al. EORTC-NCI-AACR 2002.
40PTK/ZK Changes in Ki Correlate With Changes in
Size of Liver Metastases
60
50
40
30
P .0001
20
10
Change in tumor size at day 52,
0
40
20
80
100
120
140
160
0
60
10
20
30
40
Progressors
50
Nonprogressors
Mean Baseline MRI Ki,
Day 28
41PTK/ZK Ki Correlation With Clinical Outcome
- Significant correlation between reduction in
tumor blood flow and clinical outcome after
treatment with PTK/ZK
Progressors (n 9)
1
60
P .006
Nonprogressors (n 12)
1
40
120
1
00
Mean Baseline MRI-Ki,
Mean Baseline MRI-Ki,
8
0
60
4
0
2
0
0
Day 28
Day 2
42PTK/ZK Optimal Dosing
160
Progressors
260
Day 28
240
Nonprogressors
140
220
200
120
180
100
160
140
AUC 0-24, hrµM
Mean Baseline MRI,
80
120
100
60
80
40
60
40
20
20
0
0
0
0
800
20
40
60
80
200
400
600
100
120
140
160
180
200
1,000
1,200
1,400
1,600
1,800
2,000
2,200
AUC 0-24, hrµM
Dose, mg
43Estrogen receptor imaging using
18Ffluoroestradiol (FES) -PET scanning may
predict breast cancer response to hormonal therapy
Quon, A. et al. J Clin Oncol 231664-1673 2005
44Early Response Assessment in GIST
Dec 7, 2000
Jan 1, 2001
After Gleevec
Before Gleevec
Is quantitation necessary?
45FDG PET to Assess Response
Weber, W. A. et al. J Clin Oncol 212651-2657
2003
46PET Association with Clinical Benefit
Weber, W. A. et al. J Clin Oncol 212651-2657
2003
47Overall survival according to the standardized
uptake value (SUV) for the primary tumor
Sasaki, R. et al. J Clin Oncol 231136-1143 2005
48Conclusions
- Imaging is vitally important for staging and
assessment of drug activity/tumor progression - Quantitative imaging provides information that
can be a surrogate for clinical benefit but
refinements are needed in response criteria - Functional imaging is increasingly useful for
target assessment, dose-finding and early
response assessment - Oncologists and imagers must work as partners in
cancer care and research