Imaging evaluation of clinical Imaging evaluation of clinical benefit in sarcomas: benefit in sarcomas: Dynamic MRIDynamic MRI

Dr Anwar PadhaniDr Anwar Padhanianwar.padhani@paulstrickland-scannercentre.co.ukanwar.padhani@paulstrickland-scannercentre.co.uk

Mount Vernon Cancer CentreMount Vernon Cancer Centre

LondonLondon

Montreal November 2004Montreal November 2004

Mount Vernon Cancer Centre & Mount Vernon Cancer Centre & Gray Cancer InstituteGray Cancer Institute

Royal Marsden Hospital & Royal Marsden Hospital & Institute of Cancer ResearchInstitute of Cancer Research

Janet Husband and Martin Leach, David Collins, Janet Husband and Martin Leach, David Collins, James d’Arcy, Simon Walker-Samuel, Carmel James d’Arcy, Simon Walker-Samuel, Carmel Hayes, Geoff Parker, John Suckling, Ian JudsonHayes, Geoff Parker, John Suckling, Ian Judson

I acknowledge other contributors who have provided additional materials of their work in support of this lectureI acknowledge other contributors who have provided additional materials of their work in support of this lecture

Dr H Choi, MD Andersen Cancer Cemtre, HoustonDr H Choi, MD Andersen Cancer Cemtre, HoustonDr WE Reddick, St Jude Children Research Hospital, MemphisDr WE Reddick, St Jude Children Research Hospital, Memphis

Jane Taylor, James StirlingJane Taylor, James StirlingGordon Rustin, Sue Galbraith, Kate Lankester, Gordon Rustin, Sue Galbraith, Kate Lankester, Andreas Makris, Mei-Lin Ah-SeeAndreas Makris, Mei-Lin Ah-SeeRoss Maxwell, Gill TozerRoss Maxwell, Gill Tozer

Talk outlineTalk outline

Dynamic MRI – biological basis & quantificationDynamic MRI – biological basis & quantification Illustrate utility of dynamic MRI to assess benefit Illustrate utility of dynamic MRI to assess benefit

of therapy in patients with bone sarcomasof therapy in patients with bone sarcomas– Predict response to neoadjuvant chemotherapyPredict response to neoadjuvant chemotherapy– Assess activity of residual diseaseAssess activity of residual disease

Biomarker for assessing effects of treatment with Biomarker for assessing effects of treatment with antiangiogenesis/vascular targeting drugs antiangiogenesis/vascular targeting drugs

Biomedical challenges in clinical implementation Biomedical challenges in clinical implementation specific to patients with sarcomasspecific to patients with sarcomas

Perfusion MR imaging of extracranial tumor angiogenesis. A Dzik-Perfusion MR imaging of extracranial tumor angiogenesis. A Dzik-Jurasz, Jurasz, AR PadhaniAR Padhani. Top Magn Reson Imaging. 2004;15(1):41-57.. Top Magn Reson Imaging. 2004;15(1):41-57.

Talk outlineTalk outline

Dynamic MRI – biological basis & quantificationDynamic MRI – biological basis & quantification Illustrate utility of dynamic MRI to assess benefit Illustrate utility of dynamic MRI to assess benefit

of therapy in patients with bone sarcomasof therapy in patients with bone sarcomas– Predict response to neoadjuvant chemotherapyPredict response to neoadjuvant chemotherapy– Assess activity of residual diseaseAssess activity of residual disease

Biomarker for assessing effects of treatment with Biomarker for assessing effects of treatment with antiangiogenesis/vascular targeting drugs antiangiogenesis/vascular targeting drugs

Biomedical challenges in clinical implementation Biomedical challenges in clinical implementation specific to patients with sarcomasspecific to patients with sarcomas

Perfusion MR imaging of extracranial tumor angiogenesis. A Dzik-Perfusion MR imaging of extracranial tumor angiogenesis. A Dzik-Jurasz, Jurasz, AR PadhaniAR Padhani. Top Magn Reson Imaging. 2004;15(1):41-57.. Top Magn Reson Imaging. 2004;15(1):41-57.

Dynamic contrast enhanced MRI Dynamic contrast enhanced MRI (DCE-MRI)(DCE-MRI)

Technique where Technique where enhancement of a tissue or enhancement of a tissue or organ is continuously organ is continuously monitored using MRI after monitored using MRI after bolus IV contrast mediumbolus IV contrast medium– Low molecular weight contrast Low molecular weight contrast

media (<1 kDa)media (<1 kDa)– Diffuse into extravascular-Diffuse into extravascular-

extracellular space (does not extracellular space (does not cross cell membranes)cross cell membranes)

– Experiment lasts a few minutesExperiment lasts a few minutesHaemangiopericytomaHaemangiopericytoma

Data courtesy of David Collins and Ian Data courtesy of David Collins and Ian Judson, Institute of cancer Research, Judson, Institute of cancer Research,

LondonLondon

7 minutes

Basis of dynamic contrast enhanced MRIBasis of dynamic contrast enhanced MRI

T2*W DCE-MRI of Mixed Mullerian Tumour

Typical acquisition 1-2 mins

T1W DCE-MRI of Mixed Mullerian Tumour

Typical acquisition 5-8 mins

TT22*W versus T*W versus T11W DCE-MRIW DCE-MRI

Evaluation of signal enhancement Evaluation of signal enhancement during DCE-MRIduring DCE-MRI

QualitativeQualitative - shape of signal intensity (SI) data - shape of signal intensity (SI) data curve curve

Semi-quantitativeSemi-quantitative - indices that describe one or - indices that describe one or more parts of SI or [Gd] curvesmore parts of SI or [Gd] curves Upslope gradient, max amplitude, washout rate or area Upslope gradient, max amplitude, washout rate or area

under curve at a fixed time pointunder curve at a fixed time point

True quantitativeTrue quantitative - indices from contrast medium - indices from contrast medium concentration changes using pharmacokinetic concentration changes using pharmacokinetic modellingmodelling

Type IType I(semi-necrotic with (semi-necrotic with reactive changes)reactive changes)

Type IIType II(viable tumour)(viable tumour)

Type IIIType III(rapidly proliferating (rapidly proliferating

tumour edge)tumour edge)

kep (min-1) = 0.5 kep (min-1) = 3.4 kep (min-1) = 8.9

(Taylor and Reddick, Adv Drug Del Rev, 2000)

Patterns of enhancement on TPatterns of enhancement on T11W DCE-W DCE-

MRI and histological correlatesMRI and histological correlates

Pharmacokinetic modelling of Pharmacokinetic modelling of TT11W DCE-MRI dataW DCE-MRI data

Transfer constant (KTransfer constant (Ktranstrans)) Extracellular leakage space (vExtracellular leakage space (vee)) Rate constant (kRate constant (kepep))

trans

eep

v

Kk

Modified from Tofts 1995

Quantitative analysis with Quantitative analysis with pharmacokinetic modellingpharmacokinetic modelling

AdvantagesAdvantages– Whole curve shape is analysedWhole curve shape is analysed– Biologically relevant physiological parametersBiologically relevant physiological parameters– Independent of scanner strength, manufacturer and imaging routines Independent of scanner strength, manufacturer and imaging routines – Enables valid comparisons of serial measurements and data exchange between different imaging centresEnables valid comparisons of serial measurements and data exchange between different imaging centres

DisadvantagesDisadvantages– Data acquisition and analysis is more complexData acquisition and analysis is more complex– Lack of commercial software for analysisLack of commercial software for analysis– Models may not fit the data observedModels may not fit the data observed

Clinical indications for DCE-MRI in Clinical indications for DCE-MRI in patients with musculoskeletal lesionspatients with musculoskeletal lesions

To improve characterisation of lesions*To improve characterisation of lesions* Monitoring response to treatmentMonitoring response to treatment

– Conventional treatments Conventional treatments (chemotherapy/physical treatments)(chemotherapy/physical treatments)

– Novel biological treatments including Novel biological treatments including antiangiogenic/vascular targeting drugs antiangiogenic/vascular targeting drugs

Assess activity of residual disease after Assess activity of residual disease after definitive treatmentdefinitive treatment

*Ma LD, et al. Radiology 1997; 202(3):739-44*Ma LD, et al. Radiology 1997; 202(3):739-44*van der Woude HJ et al. Radiology 1998; 208(3):821-8*van der Woude HJ et al. Radiology 1998; 208(3):821-8*Verstraete KL, Radiology. 1994; 192(3):835-43*Verstraete KL, Radiology. 1994; 192(3):835-43

Importance of predicting early Importance of predicting early tumour response to chemotherapytumour response to chemotherapy

If pathological response can be reliably If pathological response can be reliably predicted after a few cycles of neoadjuvant predicted after a few cycles of neoadjuvant chemotherapychemotherapy – Treatment regimen could be adjusted (eTreatment regimen could be adjusted (early surgery, arly surgery,

cryotherapy, isolated limb perfusion etc)cryotherapy, isolated limb perfusion etc)

Pathological response rates may be improvedPathological response rates may be improved Changing treatment could increase expense Changing treatment could increase expense

and exposes patients to greater toxicityand exposes patients to greater toxicity

There is

very l

ittle o

bjectiv

e data th

at

There is

very l

ittle o

bjectiv

e data th

at

DCE-MRI c

an predict

responses

DCE-MRI c

an predict

responses

earlyearly

after s

tating neoadjuvant c

hemothera

py

after s

tating neoadjuvant c

hemothera

py

-10.00

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

0 50000 100000 150000 200000 250000

Time (ms)

SI (B

asel

ine

Cor

rect

ed)

-20.00

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 50000 100000 150000 200000 250000 300000

Time (ms)

SI (

Bas

elin

e C

orr

ecte

d)

2 months on treatment

Pre-operative

Baseline

2 A

FDG-PET scansFDG-PET scans

Good response to treatment (99% necrosis)Good response to treatment (99% necrosis)

SUV 13.0

SUV 2.4

Courtesy of Dr H Choi, MD Andersen Cancer Center, HoustonCourtesy of Dr H Choi, MD Andersen Cancer Center, Houston

Correlation of DCE-Correlation of DCE-MRI and necrotic MRI and necrotic

fraction after fraction after

chemotherapychemotherapy

Dyke JP, et al. Radiology 2003; 228:271-278Dyke JP, et al. Radiology 2003; 228:271-278

Prognostic value Prognostic value of DCE-MRI in of DCE-MRI in osteosarcomasosteosarcomas

Disease free survival for 31 patients stratified by Disease free survival for 31 patients stratified by tumour size and DCE-MRI after 9 weeks of Rx; tumour size and DCE-MRI after 9 weeks of Rx;

Change in kChange in kepep as a function of pre-treatment as a function of pre-treatment

value. Higher permeability at presentation value. Higher permeability at presentation results in greater decreases with therapyresults in greater decreases with therapy

Reddick WE, et al. Cancer 2001; 91:2230-2237 Reddick WE, et al. Cancer 2001; 91:2230-2237

0 1 2 3 4 5 60

40

80

100

60

20

Disease-free Survival (%)

kep < 1.167 min-1

kep 1.167 min-1

Tumors < 56 cm2

0 1 2 3 4 5 60

40

80

100

60

20

Year

P = 0.05

kep < 1.167 min-1

kep > 1.167 min-1

Tumors > 56 cm2

Disease-free Survival (%)

-6

-4

-2

0

2

0 1 2 3 4 5 6 7

kep at Presentation (min-1)

kep

Du

rin

g T

her

apy

(min

-1)

Prognostic value Prognostic value of DCE-MRI in of DCE-MRI in osteosarcomasosteosarcomas

Disease free survival for 31 patients stratified by Disease free survival for 31 patients stratified by tumour size and DCE-MRI after 9 weeks of Rx; tumour size and DCE-MRI after 9 weeks of Rx;

Change in kChange in kepep as a function of pre-treatment as a function of pre-treatment

value. Higher permeability at presentation value. Higher permeability at presentation results in greater decreases with therapyresults in greater decreases with therapy

Reddick WE, et al. Cancer 2001; 91:2230-2237 Reddick WE, et al. Cancer 2001; 91:2230-2237

0 1 2 3 4 5 60

40

80

100

60

20

Disease-free Survival (%)

kep < 1.167 min-1

kep 1.167 min-1

Tumors < 56 cm2

0 1 2 3 4 5 60

40

80

100

60

20

Year

P = 0.05

kep < 1.167 min-1

kep > 1.167 min-1

Tumors > 56 cm2

Disease-free Survival (%)

-6

-4

-2

0

2

0 1 2 3 4 5 6 7

kep at Presentation (min-1)

kep

Du

rin

g T

her

apy

(min

-1)

Pre-operative

BaselineBaseline

FDG-PET scansFDG-PET scans

Poor access to contrast before treatmentPoor access to contrast before treatment

SUV 5.9

SUV 8.3

Courtesy of Dr H Choi, MD Andersen Cancer Center, HoustonCourtesy of Dr H Choi, MD Andersen Cancer Center, Houston

-5.00

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

40.00

0 50000 100000 150000 200000 250000 300000

Time (ms)

SI (

Bas

elin

e C

orr

ecte

d)

-2.00

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

0 50000 100000 150000 200000 250000 300000

Time (ms)

SI (

Bas

elin

e C

orre

cted

)Poor response to treatment (75% necrosis)Poor response to treatment (75% necrosis)

Drugs targeting tumour neovasculatureDrugs targeting tumour neovasculature

Vascular targeting drugs

Anti-VEGF drugs

PermeabilityPermeability rBVrBV

or or rBF rBF

Probably Probably depends on drug depends on drug

duration and duration and dosedose

PermeabilityPermeability rBVrBVrBFrBF

Time course of Combretastatin Time course of Combretastatin effects on microvasculature effects on microvasculature

B Vojnovic and G Tozer, Gray Cancer InstituteB Vojnovic and G Tozer, Gray Cancer Institute

Window chamber view Window chamber view P22 CarcinosarcomaP22 Carcinosarcoma

0 5 10 15 20 250

25

50

75

100

125

Time post treatment (hours)

IAP 10 mg/kg IAP 100 mg/kg

Ktrans

10 mg/kg Ktrans

100 mg/kg

Rel

ativ

e C

hang

e (%

)

IAP - radiolabelledIAP - radiolabellediodoantipyrineiodoantipyrine

2 hours post 2 hours post CA4PCA4P

PreRxPreRx

Morphological & kinetic changes Morphological & kinetic changes After 1After 1stst dose of CA4P (52mg/m dose of CA4P (52mg/m22))

24 hrs24 hrsPrePre

4 hrs4 hrsPostPost

Biologically active dose 52 mg/mBiologically active dose 52 mg/m22

Galbraith SM, et al. J Clin Oncol – Galbraith SM, et al. J Clin Oncol – 2003;21:2831-2003;21:2831-42.42.

MTD 88 mg/mMTD 88 mg/m22

DLT 114 mg/mDLT 114 mg/m22

Galbraith SM, et al. J Clin Oncol – Galbraith SM, et al. J Clin Oncol – 2003;21:2831-422003;21:2831-42

Phase I goals and DCE-MRI Phase I goals and DCE-MRI achievements in the CA4P studyachievements in the CA4P study

GoalGoal AchievementAchievement

Modulation of vascular kineticsModulation of vascular kinetics ++

Dose response relationshipDose response relationship + + (threshold)(threshold)

Identify therapeutic windowIdentify therapeutic window ++

Drug exposure kinetic response Drug exposure kinetic response relationshiprelationship

++

Galbraith SM, et al. J Clin Oncol – Galbraith SM, et al. J Clin Oncol – 2003;21:2831-422003;21:2831-42

Dose response in Ki for PTK787/ZK in Dose response in Ki for PTK787/ZK in colorectal cancer on Day 2colorectal cancer on Day 2

SEM bars, all colorectal liver metastases

No maximum tolerated dose was reached

Figure courtesy of A

Thom

as, B M

organ, Leicester R

oyal Infirmary

0

20

40

60

80

100

120

140

160

50 300 500 750 1000 1200

Dose (mg)

Ki (

% B

as

elin

e)

25 patients with 25 patients with metastatic colon cancer metastatic colon cancer evaluated at baseline, evaluated at baseline,

on day 2 and 28on day 2 and 28

Morgan, B., et al., J Clin Oncol, 2003. Morgan, B., et al., J Clin Oncol, 2003. 2121(21): p. 3955-3964.(21): p. 3955-3964.

Phase I goals and DCE-MRI Phase I goals and DCE-MRI achievements in the PTK787/ZK studyachievements in the PTK787/ZK study

GoalGoal AchievementAchievement

Modulation of vascular kineticsModulation of vascular kinetics ++

Dose response relationshipDose response relationship + + (threshold)

Identify therapeutic windowIdentify therapeutic window + + (no MTD)(no MTD)

Drug exposure kinetic response Drug exposure kinetic response relationshiprelationship

??

Morgan, B., et al., J Clin Oncol, 2003. Morgan, B., et al., J Clin Oncol, 2003. 2121(21): p. 3955-3964.(21): p. 3955-3964.

ConclusionsConclusions Dynamic MRI provides unique information on the Dynamic MRI provides unique information on the

vascular characteristics of tumoursvascular characteristics of tumours DCE-MRI can predict extent of histological DCE-MRI can predict extent of histological

response to chemotherapy in patients with response to chemotherapy in patients with osteosarcomas/Ewing tumoursosteosarcomas/Ewing tumours

Intriguingly, DCE-MRI may inform on drug access Intriguingly, DCE-MRI may inform on drug access (? predict responsiveness) and patient prognosis(? predict responsiveness) and patient prognosis

Acts as a biomarker that provides Acts as a biomarker that provides pharmacodynamic (PD) information in early trials pharmacodynamic (PD) information in early trials of antivascular drug and should be used for of antivascular drug and should be used for evaluating combination therapies in sarcomasevaluating combination therapies in sarcomas

Dynamic MR imaging of tumor perfusion: approaches and biomedical challenges. Dynamic MR imaging of tumor perfusion: approaches and biomedical challenges. DJ Collins, DJ Collins, AR PadhaniAR Padhani. IEEE Engineering in Medicine and Biology Magazine 2004. IEEE Engineering in Medicine and Biology Magazine 2004