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PET as a Biomarker inEarly Cancer Treatment Trials

Barry A. Siegel, M.D.Mallinckrodt Institute of Radiology

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Imaging to Evaluate Treatment Response

• Traditional anatomic measurement – sequential scans during and following treatment–Size change occurs slowly–Often poor reproducibility–Variable relationship with health outcome–Not feasible for all types of lesions–Anatomic response not expected with all therapies

Response Rate and Overall Survival in Phase II/III Studies of Advanced NSCLC

Data from Milton and Miller. Sem Oncol 2005

12 studies 5476 patients25 CTx regimens

R 2 = 0.3263

6789

101112

0 20 40 60

response rate (%)

med

ian

surv

ival

(m

onth

s)

Treatment of Advanced NSCLC with the EGFR Kinase Inhibitor Erlotinib

• Randomized, placebo-controlled study

• 731 patients included• Erlotinib (Tarceva,150

mg/day) vs. placebo• Response rate: 8.9%• Survival: 6.7 mo vs. 4.7

months (p<0.001)

Shephard et al. ASCO 2004; N Engl J Med, 2005

ISEL Study• Randomized, double-blind, placebo-

controlled trial• 1692 patients with metastatic NSCLC• Refractory to chemotherapy• Palliative treatment vs. the EGFR

inhibitor gefitinib (Iressa)• Objective response rate: 8.2%• Median survival:

– gefitinib: 5.6 months– placebo 5.1 months (p=0.11)

http://www.iressa.com

ISEL Study and AstraZeneca Stock Price

10% loss within 2 days

$6.58 billion

AZN NASDAQ: December 2004

ISEL results made public

Adapted from Wolfgang Weber

Monitoring Treatment of Cancer

There is a clear need for better monitoring of tumor response

• Clinically, for better patient management

• In drug development, for more efficient testing of new drugs in clinical trials

Guiding Cancer Therapy: Imaging GoalsStaging/

Characterization Therapy Outcomes

Goal 2

Identify target/ predict response

Response DFS OS

Goal 1

Prognosis: predict tumor behavior

Goal 3Measure response

Goal 4

Elucidate cancer biologyCourtesy of D. Mankoff

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Functional Imaging Modalities• Magnetic Resonance

– Magnetic Resonance Imaging (MRI)– Magnetic Resonance Spectroscopy (MRS)

• Radionuclide imaging– Positron Emission Tomography (PET)– Single-Photon Emission Computed Tomography (SPECT)

• Ultrasonography• Optical imaging

Radionuclide Imaging as a Cancer Biomarker:Measure Factors Affecting Response

Variable Levels in Tumor - Quantification!

Yu and Mankoff, Exp Rev Mol Diagn 2007; 7;659

FDG and BeyondPET Tracers for Imaging Cancer Biology

Tracer What is Measured18F-FDG glucose metabolism

18F-FES ER expression

15O-Water blood flow

18F-FLT tumor proliferation18F-FMISO, Cu-ATSM hypoxia

18F-annexin cell death

18F-RGD peptides angiogenesis

Approved Investigational Preclinical

MIR

PET Approaches for Predicting and Monitoring Response to Therapy

• Monitoring– Glucose Metabolism– Blood flow – Amino acid metabolism– DNA synthesis (proliferation)– Apoptosis

• Predicting– Chemotherapeutic agents– MDR substrates– Receptor ligands– Hypoxia tracers

MIR

Tissue Culture and Animal Models• FDG uptake related to number of viable tumor cells

– Acutely, treatment or hypoxia may increase FDG uptake

• Changes in FDG uptake parallel drug effectiveness• Dose-response relationship (chemotherapy and

radiotherapy)• Changes in FDG uptake antedate changes in tumor

volume

Assessing Treatment Response by Monitoring Glucose Metabolism with FDG:

Preclinical Studies

Su et al., Clin Cancer Res 2006; 19:5659

FDG microPET/CT before and after two p.o. doses of gefitinib

(48 hours)

• Measurement of Clinical and Subclinical Tumour Response Using [18F]-Fluorodeoxyglucose and Positron Emission Tomography: Review and 1999 EORTC Recommendations

Young et al., Eur J Cancer 1999; 13:1773

• Consensus Recommendations for the Use of 18F-FDG PET as an Indicator of Therapeutic Response in Patients in National CancerInstitute Trials

Shankar et al., J Nucl Med 2006; 47:1059

• The Netherlands Protocol for Standardisation and Quantification of FDG Whole Body PET Studies in Multi-centre Trials

Boellaard et al., Eur J Nucl Med 2009; 35:2320

• FDG PET and PET/CT: EANMProcedure Guidelines for Tumour PET Imaging

Boellaard et al., Eur J Nucl Med 2009; epub

Measurement of Tumor FDG Uptake: Technical Issues

• Patient preparation• Timing of imaging• Image acquisition and reconstruction • Definition of regions/volumes of interest• Quality control• Inter-institution cross calibration

MIR

Standardized Uptake Value

tissue conc. (µCi/gm)SUV =

inj. dose (µCi)/body weight (gm)

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Factors Affecting SUV

• Interval after injection• Success of injection (? extravasated)• Body weight (overestimated in obese patients• ROI definition (SUVmean, SUVpeak, SUVmax)• Scanner calibration (and data entry)• Resolution of scanner• Reconstruction method and filter• Blood glucose and insulin levels

Measurement of Tumor FDG Uptake: Reproducibility

• Test/re-test in 16 patients with various cancers with no intervening treatment

• Standard deviation ≈ 10% for SUV, SUVgluc, Ki, and Ki,gluc

• Change > 20% can be used to define a metabolic response

Weber et al., J Nucl Med 1999; 40:1771

Measurement of Tumor FDG Uptake: Reproducibility

Velasquez et al., J Nucl Med 2009; 50:1646

• Test/re-test in 62 patients with various GI cancers, with no intervening treatment (multi-center study)

• Greater variability than in single-center studies

• Improved with careful attention to QA and single central reader

Use of imaging data as an in vivo biomarker requires that quantitative, semi-quantitative, and qualitative endpoints reliably reflect disease status

This is achieved by:Standardization of image acquisition and processing at participating sites

Site qualificationSOPsTimely quality assurance of incoming data

Image processing and analysis at central facility under tightly controlled conditions

Rationale for Core Laboratories

• Scanner calibration incorrect in 12% (12/101)Uniform phantom SUV out of acceptable range (0.90–1.10)

• Various other problems identified

PET Facility Site Qualification

Scheuermann et al., J Nucl Med 2009; 50:1187

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Measurement of Tumor FDG Uptake

• With attention to the many factors that can affect SUV measurements and practical efforts to achieve standardization:–In individual patients, tumor SUVs are

relatively stable over time –Change in SUV is a robust parameter (each

tumor serves as its own control)

MIR

Applications of FDG-PET in Cancer Clinical Trials

• Phase I– Early assessment of anti-tumor activity

• Phase II– Better characterization of spectrum of response– Potential basis for early stopping rule at smaller

number of patients– Surrogate response marker with cytostatic agents

MIRPrice, et al., Eur J Cancer 31:1924, 1995

Potential Uses of FDG-PET in Phase I Trials

Imaging Core Laboratory

Baseline 3.5 yr1 mo24 hr

Metabolic Response to Gleevec in GIST Metabolic response precedes anatomic response

Courtesy of Annick Van Den Abbeele, M.D.

Before Hormonal Therapy

SUV=4.7 SUV=7.5

After Hormonal Therapy

Responder

SUV=5.7 SUV=5.5

Non-responder

Predicting Response to Hormonal TherapyEstradiol Challenge “Metabolic Flare”

Predicting Response to Hormonal TherapyEstradiol Challenge “Metabolic Flare”

• 51 women with advanced ER+ breast cancer

• FDG-PET before and after 30 mg estradiol x 1d

• With change ≥ 12%:PPV 100%NPV 94%

for predicting response

Dehdashti et al., Breast Cancer Res Treat 2009; 113:509N=17 N=34

Early Response to Aromatase InhibitorsWithdrawal of Agonist

Baseline After Letrozole

Coronal views, IM/sternal lesion

Adapted from D. Mankoff

>20% decrease in SUV for FDG at 2 weeks predicts:•Ki-67 <5%•Response

H. Linden et al., ASCO, 2009

FDG-PET During vs. After Radiotherapy in NSCLC

Tumor Lung

Kong et., J Clin Oncol 2007; 25:3116

Is this an appropriate biomarker to use for a response-adapted therapy strategy?

MIR

Early Assessment of Treatment Response with FDG-PET:Drug Development Issues

• Are different “metabolic response” criteria needed for different cancers and different therapies?

• Can PET measurements be made sufficiently reliably to be trusted for decision-making?

• Do PET results predict outcomes of pivotal trials?• Despite problems, PET is an attractive approach

for assessing “response” with targeted therapies

MIR

Early Assessment of Treatment Response with FDG-PET:

Clinical Challenges

• Determine “metabolic response” criteria for different cancers and different therapies

• Define how best to use the results of PET to:– Improve the outcome of non-responders

(different or more-intensive therapy)– Improve the outcome of responders

(less-intensive therapy)

PET-Guided Chemotherapy: Sample TrialBaseline FDG-PET

Rx Cycle 1

FDG-PET

Metabolic ResponseMetabolic Non-response

Alternative RxContinue Std Rx

Randomize

Follow: overall survival, progression-free survival

Less Intense RxContinue Std Rx

Randomize

Thymidine Utilization

O

CH3

N

HO

HO

NH

O

O

2'

O

CH3

N

HO

HO3PO

NH

O

O

2'

O N

HO

HO3PO

NH

O

O

2'

O N

HO

HO

NH

O

O

2'

DNA

ThymidineUdR dUMP

dTMP

ThymidineKinase

ThymidylateSynthase

DNAPolymerase

De Novo Salvage

3´-Deoxy-3´-[18F]fluorothymidine (FLT)

Shields et al., Nature Med 1998; 11:1334

Buck et al., J Nucl Med 2003; 44:1426

FLT-PET vs. FDG-PET as Measures of Proliferation in Lung Tumors

FLT FDG

r = 0.92; p < 0.0001 r = 0.59; p < 0.001

Mean SUV 1.8 Mean SUV 4.1

FLT-PET not a substitute for FDG-PET for cancer staging

FLT vs. FDG for Monitoring Tumor Response to Antiproliferative Therapy

Barthel et al., Cancer Res 2003; 63:3791 Sugiyama et al., JNM 2004; 45:1754

Chemotherapy Radiotherapy

Sohn, et al., Clin Cancer Res 2008; 14:7423

FLT-PET Imaging of ResponseGefitinib in NSCLC

Sohn, et al., Clin Cancer Res 2008; 14:7423

FLT-PET Imaging of ResponseGefitinib in NSCLC

Baseline

10 Gy

40 Gy

Everitt, et al., IJROBP 2009; 75:1104

FLT-PET Imaging of ResponseChemoradiation of NSCLC

Francis et al. Gut 2003; 52:1602-6

1818FF--FDG FDG 1818FF--FLTFLT

FDG vs. FLT: Colorectal Cancer

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PET Approaches for Assessing Response to Therapy

• Monitoring– Glucose Metabolism– Blood flow – Amino acid metabolism– DNA synthesis (proliferation)– Apoptosis

• Predicting– Chemotherapeutic agents– MDR substrates– Receptor ligands– Hypoxia tracers

Radiotracer Imaging of Hormone-Responsive Cancers

Potential Response (surrogate)

RECEPTOR

Signal Transduction

CELLULAR RESPONSE

CLINICAL OUTCOME

?

Hormone Drug "Agonist" "Antagonist"

FDGFatty Acids

Amino Acids NucleosidesFES

Ligand Uptake

DNA SynthesisProtein SynthesisMetabolism

F-18-Fluoroestradiol (FES):PET Estrogen Receptor (ER) Imaging

FES Estradiol

HO

OH

HO

OH

F*

Kieswetter, J Nucl Med, 1984

RBA (FES vs Estradiol)

ER 0.9SHBG 0.8

FES-PET Provides a QuantitativeEstimate of ER Expression

Mintun, et al., Radiology 1988; 169:45,

ER Concentration(fmoles/mg protein)

Tum

or U

ptak

e(%

ID/m

L x

10-4

)

50 100 150 2000

2

6

4

8

0

Peterson, et al., J Nucl Med 2008; 49:367

vs Radioligand Binding vs Immunohistochemistry

FES Uptake Predicts Breast Cancer Response to Hormonal Therapy

Pre-Rx Post-Rx

FES FDG FDG• Newly

diagnosed stage IV cancer

• ER+ primary

• FES- negative bone lesions

No responseto several hormonal therapies

• Recurrent sternal lesion

• ER+ primary

• Recurrent tumor strongly FES+

Excellent responseafter 6 wks Letrozole

Linden, J Clin Oncol 2006; 24:2793Courtesy of D. Mankoff

FES Uptake Predicts Response of Advanced Breast Cancer to Hormonal Therapy

Mortimer, J Clin Oncol, 2001

0

2

4

6

8

10 HER2 NegHER2 Pos

Non-RespondersResponders

LABC or Metastatic Br CA Primary Tamoxifen Rx

Recurrent or Metastatic Br CA Aromatase Inhibitor Rx

(P < .01 for both)

FES

SUV

Linden, J Clin Oncol, 2006

FES

SUV

Responders Non-Responders

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Tumor Hypoxia• Hypoxic components in most solid animal tumors and

presumably most human tumors• Increases local tumor aggressiveness and metastatic

potential• Results in resistance to radiotherapy and chemotherapy• Radioresistance potentially overcome by use of high-

LET radiation, hyperbaric oxygenation, hyperthermia, or hypoxic-cell radiosensitizers, but effectiveness may be limited by patient selection

• Several different PET tracers available for detection and quantification

PET Imaging Agents PET Imaging Agents –– Cu(ATSM)Cu(ATSM)

Basic Science:

Uptake

Time

Single Cell Suspension Assay

Hypoxic Cells

Normal CellsUptake

Time

PET Imaging of Tumor-Bearing RodentHypoxic Tumor

NormoxicTumor

IMAGEABLE DIFFERENCE

Theory:Theory:

TRAPPEDTRAPPED

Hypoxic cell (Hypoxic cell (--OO22))

CHCH33

HNHN

CHCH33

NHNH

HH33CC

NN NN

SHSH

CHCH33

NN NN

HSHS

CuCuCuCu

HH33CC CHCH33

NN NN NN NN

CHCH33

HNHN

CHCH33

NHNHSSSS

NOTTRAPPED

NOTTRAPPED

CuCu

HH33CC CHCH33

NN NN NN NN

CHCH33

HNHN

CHCH33

NHNHSSSS

Normal cell (+ONormal cell (+O22))

CuCu

HH33CC CHCH33

NN NN NN NN

CHCH33

HNHN

CHCH33

NHNHSSSS

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6060CuCu--ATSM: Cervical CancerATSM: Cervical CancerFDG60Cu-ATSM

T/M = 3.0

Responder

T/M = 4.5Non-responder

Dehdashti et al., JNM 2008; 49:210

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60Cu-ATSM: Cervical Cancer

Dehdashti et al., JNM 2008; 49:210

Imaging to Direct Hypoxia-Specific Treatment

• Advanced head and neck cancer• Randomized to

– XRT + Cisplatin/5-FU– XRT + Cisplatin/Tirapazamine

• FMISO-PET (observational only)

FDG-PET

FMISO-PET

Time to Locoregional Failure

Rischin, et al., J Clin Oncol 2006; 24:298

FMISO+/5FU

FMISO+/TPZ

PET as a Biomarker in Early Cancer Treatment Trials: Summary

• Functional/molecular imaging provides new information in early drug trials, e.g.,

– Target identification– Response & pharmacodynamics for targeted therapy

• Improve patient selection– Is target present?

• Early evaluation of efficacy– Was target hit? (proof of mechanism)– Is tumor responding?

• Key component of Phase I/II programs in the future