Anwar Padhani MD

Mount Vernon Hospital Cancer Centre

London, UK

Monitoring bony metastases response with diffusion MRI

Objectives

�� To illustrate the potential of whole body DWI in the therapy resTo illustrate the potential of whole body DWI in the therapy response ponse

assessment of bone metastasesassessment of bone metastases

�� To illustrate that there are 4 patterns of response when signal To illustrate that there are 4 patterns of response when signal

intensity and ADC values are evaluated intensity and ADC values are evaluated

�� To provide advice on how to use WBTo provide advice on how to use WB--DWI in conjunction with DWI in conjunction with

anatomic MRI to successfully gauge bone marrow therapy responseanatomic MRI to successfully gauge bone marrow therapy response

• Kwee TC, et al. Whole-body diffusion-weighted MRI. Eur J Radiol 2009; 70:409–417

• Padhani AD, Koh DM, Collins D. Whole body diffusion MR imaging in cancer – current status and

research directions. Radiology – in press

•Padhani AR & Koh DM. Diffusion MRI for monitoring of treatment response. MRI Clin N Am 2011; 19:

181-209

• Padhani AR & Gogbashian A. Bony metastases - assessing response to therapy with whole body

diffusion MRI. Cancer Imaging 2011; - in press

Monitoring bone therapy response

�� Symptoms assessments (analgesic requirements) and development ofSymptoms assessments (analgesic requirements) and development of

skeletal related events are markers of therapeutic efficacy in cskeletal related events are markers of therapeutic efficacy in clinical trials linical trials

�� Serum markers are not useful for therapy response for the majoriSerum markers are not useful for therapy response for the majority of ty of

tumors that metastasize to bonetumors that metastasize to bone

–– Serum PSA: not reliable in late stage hormoneSerum PSA: not reliable in late stage hormone--refractory prostate disease; refractory prostate disease;

flare phenomenon in responding patients*flare phenomenon in responding patients*

–– CA15CA15--3: moderate sensitivity for metastatic disease (603: moderate sensitivity for metastatic disease (60--65%); flare reaction in 65%); flare reaction in

responding breast cancer patients**responding breast cancer patients**

�� Serum/urinary markers of osteoblastic and osteoclastic activity Serum/urinary markers of osteoblastic and osteoclastic activity monitor monitor

bone response bone response NOTNOT tumor responsetumor response

�� Circulating tumor cells (CTCs) are emerging as strong response bCirculating tumor cells (CTCs) are emerging as strong response biomarkers iomarkers

for breast, colorectal and prostate cancersfor breast, colorectal and prostate cancers

**ScherScher HI et al. JCO 2008; 26:1148HI et al. JCO 2008; 26:1148--5959

**Duffy MJ. **Duffy MJ. ClinClin ChemChem 2006; 52:3452006; 52:345--5151

Evaluating bony disease by MRI: combining sequences into whole body examinations

� T1-weighted spin-echo, T2-weighted (FS) & STIR– Cellular and water content

� T2*-weighted GRE (IP/OP)– Fat:water ratio and susceptibility induced by trabecular bone

� Dynamic contrast enhanced MRI– Vascularisation

� Ultrashort TE (UTE)– Trabecular bone structure

� DW-MRI– Perfusion, cell density, fat and water content

* * Schaefer JF, et al. TotalSchaefer JF, et al. Total--body MRbody MR--imaging in oncology. imaging in oncology. EurEur RadiolRadiol. 2006; 16(9):2000. 2006; 16(9):2000--15.15.

* Schmidt GP, et al. Whole* Schmidt GP, et al. Whole--body MRI for the staging and followbody MRI for the staging and follow--up of patients with metastasis. up of patients with metastasis. EurEur

J J RadiolRadiol 2009; 70: 3932009; 70: 393––400400

Whole body DWI for metastasis detection

�� Widespread availabilityWidespread availability

�� Better than CT scans and bone Better than CT scans and bone

scans for lytic bony diseasescans for lytic bony disease

�� AlsoAlso provides information about provides information about

soft tissue diseasesoft tissue disease

�� AdvantagesAdvantages

–– No ionizing radiationNo ionizing radiation

–– No injections of isotopes or contrast No injections of isotopes or contrast

mediummedium

–– Quick to perform & readQuick to perform & read

–– QuantitativeQuantitative

�� At a glance assessmentsAt a glance assessments

→→ Improves whole body MRI Improves whole body MRI

performanceperformance

Kwee TC, et al. WholeKwee TC, et al. Whole--body diffusionbody diffusion--weighted MRI. weighted MRI. EurEur J J RadiolRadiol 2009; 70: 4092009; 70: 409––417417

WB-DWI sub-protocol(STIR for FS – total 25mins)

CoilsCoils surfacesurface

FOV (cm)FOV (cm) 380380

Rectangular (%)Rectangular (%) 100100

Acquisition matrixAcquisition matrix 128i128i

Scan %Scan % 8080

SlicesSlices 5050

Thickness/gapThickness/gap 5/05/0

ZZ--axis coverage (cm)axis coverage (cm) 2525

TR (ms)TR (ms) 90009000

TE (ms)TE (ms) min ( 67)min ( 67)

TI (ms)TI (ms) 180180

Half scan factorHalf scan factor 6/8i6/8i

bb--valuesvalues 50, 90050, 900

NENE 66

Bandwidth (Hz/Bandwidth (Hz/pixpix)) 16281628

Scan time/station (Scan time/station (minsmins)) 6.156.15

b50b50 b900b900

4 stations; 50 slices, 4 stations; 50 slices,

5mm; b50, b9005mm; b50, b900Scouts; T1W/STIRScouts; T1W/STIR

Whole bodyWhole body

Normal bone marrow pattern

� Normal adult BM distribution established by 25 yo

– Yellow bone marrow: 10-20% water, fat cells (↓SI)

– Red bone marrow: 40-60% water & more cells (↑SI)

� Variable red BM atrophy and trabecular bone loss

after 40 yo (>♀)

→ Increase in yellow bone marrow

Normal adult BM Normal adult BM

distributiondistribution

NonNon--linear (paradoxical) linear (paradoxical)

relationship between ADC & relationship between ADC &

bone marrow cellularitybone marrow cellularity

�� Yellow (fatty) marrow Yellow (fatty) marrow →→ low low

SI & ADCSI & ADC

-- Low water content & cellularityLow water content & cellularity

-- Fat acts as a barrier to water Fat acts as a barrier to water

diffusion repelling waterdiffusion repelling water

-- Low perfusionLow perfusion

�� Red bone marrow Red bone marrow →→ higher SI higher SI

& ADC & ADC

-- More cells and waterMore cells and water

-- Less big fat cells & more small cellsLess big fat cells & more small cells

-- Higher perfusionHigher perfusion

�� TumorTumor & BM hyperplasia& BM hyperplasia →→highest SI but variable ADC highest SI but variable ADC

-- Highest water content & cellularity Highest water content & cellularity

within restricted bone marrow spacewithin restricted bone marrow space

-- Highest perfusionHighest perfusion

Assessing WBAssessing WB--DWI response to RxDWI response to Rx

�� Changes in tumor burden/volumeChanges in tumor burden/volume

�� Changes in signal intensity on high bChanges in signal intensity on high b--value imagesvalue images

–– Reflects changes in water diffusivity Reflects changes in water diffusivity andand water contentwater content

�� Changes in ADC valuesChanges in ADC values

–– Objective evaluations of water diffusivityObjective evaluations of water diffusivity

–– Amenable to numerical analysis Amenable to numerical analysis

–– Heterogeneity assessments are made possibleHeterogeneity assessments are made possible

•• Histogram & pixel map analyses (parametric response maps)Histogram & pixel map analyses (parametric response maps)

Hamstra DA, et al, J Clin Oncol 2007: 25:4104-4109

Biological processes involved in therapy induced changes in DWI

25/Mar/10 2/Dec/10

Multiple Myelomacyclophosphamide, dexamethasone, thalidomide (CDT) and bortezomib

Prior

Current

WBWB--DWIDWI

Metastatic bone disease: Metastatic bone disease:

not responding to therapynot responding to therapy

�� New areas of focal abnormal signal intensityNew areas of focal abnormal signal intensity

�� Increasing extent (becoming confluent) and intensity of Increasing extent (becoming confluent) and intensity of

lesionslesions

�� For BM disease ADC values can For BM disease ADC values can ↓↓, , ↔↔ or or ↓↓(heterogeneous; but (heterogeneous; but

remains below thresholds)!remains below thresholds)!

Signal intensity changes in nonSignal intensity changes in non--responseresponse

47 47 yoyo F F –– metastatic breast cancer 1metastatic breast cancer 1stst Taxanes/APD then Taxanes/APD then LetrozoleLetrozole

1111--33--1010 88--66--1010 88--99--1010

b800b800 b800b800 b800b800

Increases in Increases in

tumour volume & tumour volume &

ADC values with ADC values with

progressionprogression

�� 51 51 yoyo F metastatic F metastatic

breast cancerbreast cancer

�� Bone and liver diseaseBone and liver disease

�� Pre and post Taxanes/ Pre and post Taxanes/

APD/ Herceptin APD/ Herceptin

�� Bone tumor volume Bone tumor volume

29.3 29.3 →→ 179.2 cm179.2 cm33

�� ADC 780 ADC 780 →→ 930 930 μμmm22/s/s

DWDW--MRI and cellularity in bone marrow MRI and cellularity in bone marrow A

DC

AD

C

Signal intensity on high bSignal intensity on high b--value imagesvalue images

Dense malignant infiltration>80% H20

Yellow marrowYellow marrow

10% H10% H2200Hyperplastic/moderate

tumour infiltration60-80% H20

Red marrowRed marrow

4040--60% H60% H2200

NonNon--

effective Rxeffective Rx

Disease progression can cause modest increases, stable or slightDisease progression can cause modest increases, stable or slight

decreases in ADCdecreases in ADC

BM hyperplasia: increased SI but stable ADC40 F – post-partum, left mastectomy and axillary nodal dissection

PRIORPRIOR

CURRENTCURRENT30-July 2010 10-December-2010

ADC 920 ADC 920 ±± 266 266 →→ 920 920 ±± 211 211 µµmm22/s/s

Rx adjuvant chemotherapy with G-CSF support

Myeloma progressionMyeloma progression

↑↑ SI & SI & ↓↓ADCADC

STIRSTIR T1WT1W

1111thth JanJan

11stst AprilApril

b800b800 ADCADC

1111thth JanJan

11stst AprilApril

1111--JanJan--1010 11--AprilApril--1010

62M Multiple Myeloma 62M Multiple Myeloma –– Rx BortezomibRx Bortezomib

1111--JanJan--1010 11--AprilApril--1010

900 900 µµmm22/s/s

725 725 µµmm22/s/s

Variable changes in ADC in nonVariable changes in ADC in non--

responders (stable + progression)responders (stable + progression)

�� 26 patients with 26 patients with

metastatic prostate metastatic prostate

cancercancer

�� ChemotherapyChemotherapy

�� 100 lesions 100 lesions

–– 33 in responders33 in responders

–– 59 in progressors 59 in progressors

–– 8 stable8 stable

�� Limits of reproducibility Limits of reproducibility

of normal BM of normal BM ±± 86 86 µµmm22/s/s

Messiou C, et al. Assessing response in bone metastases in prostMessiou C, et al. Assessing response in bone metastases in prostate cancer with diffusion ate cancer with diffusion

weighted MRI. weighted MRI. EurEur RadiolRadiol 2011 2011 –– ahead of printahead of print

Limits of

reproducibilityCh

an

ge

in

AD

C (

µm

2/s

)

Courtesy of C. Messiou, Royal Marsden Hospital, London

-600

-400

-200

0

200

400

600

800

1000

1200

Ch

an

ge in

AD

C (

um

2/s

)

Responders

Progressors

Stable patients

WBWB--DWIDWI

Bony diseaseBony disease

responding to therapyresponding to therapy

�� Decrease in volume of focal abnormal signal intensityDecrease in volume of focal abnormal signal intensity

�� Signal intensity changes generally decrease but occasionally Signal intensity changes generally decrease but occasionally

unchanged/increase if there is a strong inflammatory response unchanged/increase if there is a strong inflammatory response

�� ADC values : marked increasesADC values : marked increases

Breast cancer (triple negative)Breast cancer (triple negative)Rx Rx GemCarboGemCarbo + APD (bisphosphonate)+ APD (bisphosphonate)

0101--OctOct--20102010

T1WT1W T2W+FST2W+FS WBWB--DWIDWI

b900b900

2929--JulyJuly--20102010

T1WT1W T2W+FST2W+FS WBWB--DWIDWI

b900b900

Decreases in DW-MRI is due to a combination of changes in tissue water content and cellularity

�� 37F 37F –– perimenopausalperimenopausal

�� Triple negative, Triple negative, metastatic breast cancermetastatic breast cancer

�� Rx Rx –– GemCarboGemCarbo plus APDplus APD

�� Diffuse increase in ADC Diffuse increase in ADC valuesvalues

�� ADC 883 ADC 883 →→ 1905 1905 μμmm22/s/s

�� CutCut--off values: 650 & off values: 650 & 1500 1500 μμmm22/s/s

2929--JulyJuly--20102010 0101--OctOct--20102010

b900b900

ADCADC

Prior

Current

Breast cancer (triple negative)Breast cancer (triple negative)Rx Rx GemCarboGemCarbo + APD (bisphosphonate)+ APD (bisphosphonate)

AD

CA

DC

Signal intensity on high bSignal intensity on high b--value imagesvalue images

Dense malignant infiltration>80% H20

Yellow marrowYellow marrow

10% H10% H2200Hyperplastic/moderate

tumour infiltration60-80% H20

Red marrowRed marrow

4040--60% H60% H2200

NonNon--

effective Rxeffective Rx

Effective Rx

Decreasing cellularity

Breast cancerBreast cancer

Rx Rx Capecitabine (3 cycles) + APD(3 cycles) + APD

2121--JanJan--20112011

T1WT1W T2W+FST2W+FS b900b900

0404--AprilApril--20112011

T1WT1W T2W+FST2W+FS b900b900

Breast cancerBreast cancerRx Rx capcitabinecapcitabine + +

APDAPD

�� 41F 41F –– postmenopausalpostmenopausal

�� Metastatic breast cancer Metastatic breast cancer --asymptomatic (before and asymptomatic (before and during Rx)during Rx)

�� Rx Rx –– cepcitabinecepcitabine (3 cycles) plus (3 cycles) plus APDAPD

�� Signal intensity is unchanged but Signal intensity is unchanged but marked increase in ADC valuesmarked increase in ADC values

�� ADC ADC →→ mean 900 to 1500 mean 900 to 1500 μμmm22/s/s

�� CutCut--off values: 650 & 1500 off values: 650 & 1500 μμmm22/s/s

2121--JanJan--20112011 0404--AprilApril--20112011

b900b900

ADCADC

CurrentCurrentPriorPrior

AD

CA

DC

Signal intensity on high bSignal intensity on high b--value imagesvalue images

Yellow marrowYellow marrow

10% H10% H2200Dense malignant

infiltration>80% H20

Hyperplastic/moderate tumour infiltration

60-80% H20

Red marrowRed marrow

4040--60% H60% H2200

NonNon--

effective Rxeffective Rx

Effective Rx

Decreasing cellularity NecrosisNecrosis

(T2(T2--shine through)shine through)

Response with GemCarbo+bisphosphonates → relapse after stopping Rx

Progression with bisphosphonates → response with docetaxel + bisphosphonates

23/Jul/10 1/Oct/10 20/Apr/118/Feb/1115/Dec/10

5/Jan/10 6/Apr/10 30/Jul/10 28/Oct/10 1/Mar/11

Proposed response criteria of BM lesionsEARLY after starting cytotoxic Rx

SI on high b-

value images

ADC in relation

cut-off

Biological inference and

response assessment

↑ Most pixels <cut-off Persistent hypercellularity → no

evidence of response

↑ Most pixels >cut-off Necrosis, T2-shine through → evidence

of response

↓ Most pixels >cut-off Hypocellularity → evidence of response

↓ Most pixels <cut-off Possible sclerotic or fibrotic reaction →

indeterminate for response

ADC change needs to be judged in relation to cutADC change needs to be judged in relation to cut--off values defined from untreated patients off values defined from untreated patients

examined using the same imaging protocol. This is likely to be texamined using the same imaging protocol. This is likely to be tumor type dependent. umor type dependent.

Criteria may not apply to nonCriteria may not apply to non--cytotoxic therapies. The timeline for the applicability of thesecytotoxic therapies. The timeline for the applicability of these

criteria are undefined criteria are undefined

Padhani AR & Gogbashian A. Bony metastases Padhani AR & Gogbashian A. Bony metastases -- assessing response to therapy with assessing response to therapy with

whole body diffusion MRI. Cancer Imaging 2011; whole body diffusion MRI. Cancer Imaging 2011; -- in pressin press

Some outstanding R&D questionsSome outstanding R&D questions

�� It is not clear what proportion of tumor cells have to be killedIt is not clear what proportion of tumor cells have to be killed for for

ADC changes to become detectable by DWADC changes to become detectable by DW--MRIMRI

–– Does the mechanism of cell death affect DWDoes the mechanism of cell death affect DW--MRI appearances? MRI appearances?

�� What is the reproducibility of WBWhat is the reproducibility of WB--DWI ADC estimates (that is, how DWI ADC estimates (that is, how

much of measured change can be considered much of measured change can be considered ““realreal””??

–– What factors affect the measurement reproducibility?What factors affect the measurement reproducibility?

→→ Essential information for the development of WBEssential information for the development of WB--DWI as a DWI as a

pharmacodynamic biomarker for use in drug trialspharmacodynamic biomarker for use in drug trials

�� How much change in ADC results in patient benefit (improvements How much change in ADC results in patient benefit (improvements

in symptoms and survival) for the variety of available therapiesin symptoms and survival) for the variety of available therapies??

→→ Essential information for the development of WBEssential information for the development of WB--DWI as a tool for DWI as a tool for

personalized medicinepersonalized medicine

Padhani AR, Koh DM & Collins D. Padhani AR, Koh DM & Collins D. Whole body diffusion MRI in cancer Whole body diffusion MRI in cancer -- current status & current status &

research directionsresearch directions. Radiology . Radiology -- in pressin press

Take home pointsTake home points

�� WBWB--DWI is a SI based tool for DWI is a SI based tool for bone marrow lesion bone marrow lesion

detection and therapy responsedetection and therapy response

–– Lytic bone deposits are better seen than sclerotic lesionsLytic bone deposits are better seen than sclerotic lesions

�� NonNon--linear (paradoxical) relationship between ADC & bone linear (paradoxical) relationship between ADC & bone

marrow signal intensitymarrow signal intensity

–– Disease progression causes heterogeneous changes in ADCDisease progression causes heterogeneous changes in ADC

–– Response assessments Response assessments →→ larger ADC increases larger ADC increases

�� WBWB--DWI should always be interpreted with conventional DWI should always be interpreted with conventional

imaging findingsimaging findings

�� WBWB--DWI has not yet been proven to impact meaningful health DWI has not yet been proven to impact meaningful health

outcomes in patients with metastatic bone diseaseoutcomes in patients with metastatic bone disease

Padhani AR & Gogbashian A. Bony metastases Padhani AR & Gogbashian A. Bony metastases -- assessing response to therapy with assessing response to therapy with

whole body diffusion MRI. Cancer Imaging 2011; whole body diffusion MRI. Cancer Imaging 2011; -- in pressin press