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!

You have to see it before you can measure it!

CT helps in the removal of most structure noise

case ctn048, ctn008 - section 17

lungnodule

Vast Amount of Data

From S. Armato

Erasmus, J. J. et al. J Clin Oncol; 21:2574-2582 2003

Measurable?

Erasmus, J. J. et al. J Clin Oncol; 21:2574-2582 2003

Measurable?

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

Enzinger, P. C. et al. N Engl J Med 2003;349:2241-2252

PET-CT Staging of Esophageal Cancer

Lardinois, D. et al. N Engl J Med 2003;348:2500-2507

PET-CT Staging of NSCLC

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

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r si

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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

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1,00

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1,20

0

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0

1,60

0

1,80

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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?

Weber, W. A. et al. J Clin Oncol; 21:2651-2657 2003

FDG PET to Assess Response

Weber, W. A. et al. J Clin Oncol; 21:2651-2657 2003

PET Association with Clinical Benefit

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