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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
The Role of Imaging in Oncology
• Detection
• Staging (assess prognosis)
• Treatment planning
• Assess response/progression (assess benefit)
• Monitor recurrence
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?
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
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
Activity vs. Benefit
• Don’t 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
Survival
• Unambiguous endpoint that is not subject to investigator interpretation or bias from unblinded studies
• Assessed easily, frequently
• No tumor measurements required!!
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
Response Criteria
• WHO: PR is > 50% decrease in the sum of the product of the perpendicular diameters of measurable lesions
• RECIST: PR is > 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
Criteria for Progression
• WHO: PD is > 25% increase in the sum of the product of the perpendicular diameters of measurable lesions (40% increase in volume)
• RECIST: PD is > 20% in the sum of the longest diameters of target lesions (73% increase in volume)
• RECIST is biased toward stable disease
What is Measurable?
• Lesion measured in one dimension as > 20 mm with conventional techniques or > 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!
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
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
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?
BAY 43-9006: RDTTrial Schema
> 25% Tumor
shrinkage
-25% to +25%Tumor
stabilization
> 25%Tumor growth
BAY 43-900612 weekrun-in
ContinueBAY 43-9006
Continue BAY 43-9006
12 weeks
Placebo*12 weeks
Off study
% SD24 weeks
*Placebo pts with PD may cross over to BAY 43-9006
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
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
BAY 43-9006 (sorafenib) Study RCC Bidimensional Tumor Measurements* at Week 12:
Change from Baseline in Target Lesions (n=89)%
Ch
an
ge
in
Tu
mo
r M
ea
su
rem
en
t
Number of Patients
> 25% Growth
< 25% to >-25% Change
>-25% to -49% Shrinkage
> -50% Shrinkage
7
45** 24 13
* Investigator assessed
* * 7 of 45 patients not randomized
Response vs. Stable Disease
• The distinction between “minor responses” and partial responses is based on arbitrary criteria
• The patient doesn’t care whether the tumor shrank by 40% (bidimensional) or 60%– So why should we?
BAY 43-9006 (sorafenib) Study Progression-Free Survival in RCC Patients Continuing
Beyond Initial 12 Weeks
* Responders at 12 week assessment with >25% tumor shrinkage
12 Weeks 24 Weeks
Open Label BAY (n=37)Median = 48 weeks(88% progression free at 24 weeks)
Randomized (n=38) Median = 23 weeks(41% progression free at 24 weeks)
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
• Tumor assessment frequency should be the same across study arms even when cycles are of different lengths
Time to Progression Measurement Considerations
• Minimum interval between tumor assessments should be less than the expected treatment effect size
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
ResponseResponse
PD at 18 wksPD at 18 wks
TTP Better Categorizes Tumor Control Than Response Rate
Progressive DiseaseProgressive Disease
PD at 6 wksPD at 6 wks
00
1010
2020
3030
4040
5050
6060
7070
8080
00 66 1212 1818 2424 3030 3636 4242 4848 5454
Time (weeks)Time (weeks)
To
tal T
arg
et T
um
or
Len
gth
(cm
) T
ota
l Tar
get
Tu
mo
r L
eng
th (
cm)
Response StatusResponse Status Stable DiseaseStable Disease
PD at 54 wksPD at 54 wks
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
DCE MRI in CRC Patient Treated with PTK 787
Ki dropped from 100% baseline to: 31% on day 234% at end cycle 115% at end cycle 2
Baseline Day 2
Thomas et al. EORTC-NCI-AACR 2002.
PTK/ZK: Changes in Ki Correlate With Changes in Size of Liver
Metastases
Mean Baseline MRI Ki, %Day 28
20 40 60 80 100 120 140 160
60
50
40
30
20
10
0
– 10
– 20
– 30
– 40
– 50Ch
ang
e in
tu
mo
r si
ze a
t d
ay 5
2, %
0
Progressors
Nonprogressors
P = .0001
0
20
40
60
80
100
120
140
160P = .006
• Significant correlation between reduction in tumor blood flow and clinical outcome after treatment with PTK/ZK
PTK/ZK: Ki Correlation With Clinical Outcome
0
Progressors (n = 9)
Nonprogressors (n = 12)
160
140
120
100
80
60
40
20Mea
n B
asel
ine
MR
I-K
i, %
Day 2 Day 28
Mea
n B
asel
ine
MR
I-K
i, %
PTK/ZK: Optimal DosingM
ean
Bas
elin
e M
RI,
%
160
140
120
100
80
60
40
20
0
0 20 40 60 80 100
120
140
160
180
200
Progressors
Nonprogressors
AUC 0-24, hr•µM
260
240
220
200
180
160
140
120
100
80
60
40
20
0
Dose, mg
Day 28
0
200
400
600
800
1,00
0
1,20
0
1,40
0
1,60
0
1,80
0
2,00
0
2,20
0
AU
C 0
-24,
hr•
µM
Quon, A. et al. J Clin Oncol; 23:1664-1673 2005
Estrogen receptor imaging using [18F]fluoroestradiol (FES) -PET scanning may predict breast cancer response
to hormonal therapy
Early Response Assessment in GIST
Dec 7, 2000 Jan 1, 2001
After Gleevec™
Before Gleevec™
Is quantitation necessary?
Sasaki, R. et al. J Clin Oncol; 23:1136-1143 2005
Overall survival according to the standardized uptake value (SUV) for the primary tumor
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