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Imaging evaluation of clinical benefit in sarcomas: Dynamic MRI. Dr Anwar Padhani anwar.padhani@paulstrickland-scannercentre.co.uk Mount Vernon Cancer Centre London. Montreal November 2004. Mount Vernon Cancer Centre & Gray Cancer Institute. Royal Marsden Hospital & - PowerPoint PPT Presentation
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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
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
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