The Need for Quantitative Imaging in Oncology

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The 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

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The Role of Imaging in Oncology

• Detection
• Staging (assess prognosis)
• Treatment planning
• Assess response/progression (assess benefit)
• Monitor recurrence

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The 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?

4
Clinical 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

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Clinical 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

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Activity 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

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Survival

• Unambiguous endpoint that is not subject to
  investigator interpretation or bias from
  unblinded studies
• Assessed easily, frequently
• No tumor measurements required!!

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Response 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

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Response 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

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Criteria 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

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What 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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You have to see it before you can measure it!
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CT helps in the removal of most structure noise
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case ctn048, ctn008 - section 17
Vast Amount of Data
From S. Armato
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Measurable?
Erasmus, J. J. et al. J Clin Oncol 212574-2582
2003
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Measurable?
Erasmus, J. J. et al. J Clin Oncol 212574-2582
2003
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Is 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

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Is 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

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Is 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?

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BAY 43-9006 RDTTrial Schema
gt 25 Tumorshrinkage
-25 to 25Tumor stabilization
BAY 43-9006 12 week run-in
gt 25Tumor growth
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BAY 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

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BAY 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
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Response 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?

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BAY 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
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Time 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

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Time 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

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Time 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

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TTP Better Categorizes Tumor Control Than
Response Rate
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How 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

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PET-CT Staging of Esophageal Cancer
Enzinger, P. C. et al. N Engl J Med
20033492241-2252
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PET-CT Staging of NSCLC
Lardinois, D. et al. N Engl J Med
20033482500-2507
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DCE 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.
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PTK/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
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PTK/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
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PTK/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
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Estrogen 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
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Early Response Assessment in GIST
Dec 7, 2000
Jan 1, 2001
After Gleevec
Before Gleevec
Is quantitation necessary?
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FDG PET to Assess Response
Weber, W. A. et al. J Clin Oncol 212651-2657
2003
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PET Association with Clinical Benefit
Weber, W. A. et al. J Clin Oncol 212651-2657
2003
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Overall survival according to the standardized
uptake value (SUV) for the primary tumor
Sasaki, R. et al. J Clin Oncol 231136-1143 2005
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Conclusions

• 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