whitney pope, md, phd director of neuro core, medqia director of brain tumor imaging, assistant...

Whitney Pope, MD, PhD

Director of Neuro Core, MedQIADirector of Brain Tumor Imaging,

Assistant Professor of Neuroradiology,University of California, Los Angeles

XL184-205 Investigator MeetingJune 3rd, 2010

Scientific Aspect ofGB Imaging

XL184-205 Investigator Meeting - Confidential 2

Outline

• 1,


Astrocytoma: grade IV - GBM

GBM: 2 year survival - 24%5 year survival – 0%

If grade III has imaging evidence of necrosis: same survival curve as GBM

At UCLA

Low on T1Bright on T2Almost always enhances+/- Necrotic

Brain slicePathology

T1 + contrast T2


A, Axial post-contrast T1-weighted images of a patient with GBM: necrosis

B, Axial T2-weighted images from the same patient. High T2W signal surrounds the tumor: vasogenic edema

C, Axial post-contrast T1-weighted images of another GBM patient: necrosis

D, Axial T2-weighted images of the same patient in (C): non-enhancing tumor (nCET)

Appearance of GBM on MRI

A B

C D


Examples of “Typical” GBM

Enhancing, Necrotic Tumor

T1 Post Contrast T2


Example of Enhancing versus Non-Enhancing Tumor

FLAIR T2

Non-enhancing and enhancing tumor Non-enhancing tumor

T1 Post Contrast

Enhancing tumor

Vasogenic edema


FLAIR Can Improve Tumor Visualizationinsert slide to encourage dwi

T2 FLAIR

Tumor

Insert next slide a dwi slide to encourage this is done


T2 versus FLAIR: More examples

Tumor and edema

Tumor only

T2 FLAIR


Examples of non contrast enhancing tumor GBM

Non-enhancing GBM showing biopsy site

Intraventricular GBM with enhancing and non-enhancing tumor

GB

M I

mag

ing


Role of Imaging in Clinical Trials

• Imaging plays an important role in all Clinical trials– Phase I

Primary goal tolerated dose Imaging exploratory

o Mechanism of actiono Pilot efficacy

– Phase III Primary goal overall survival Imaging

o used at clinical sites to manage patientso Secondary endpoints


Challenges in GBM assessment

– Phase II goal therapeutic effect Imaging is a primary endpoint

o ( radiographic response + with clinical status)

• Substantial challenges in Radiologic

evaluation of tumor size during clinical trials

• Critical Role of IRF to standardize– Image acquisition

Across sites Across time lines

– Assessment of tumor burden


Challenges in GBM assessment

• Challenges include:• – Technical imaging considerations (Please add

slides, move slide 39)• – Selection of lesions (Please add slides)• – Measurement approaches (Discuss confluence and

splitting lesions, also measuring multi nodular lesions, measuring around surgical cavity…)

• – Response criteria • – Interval between tumor measurements and

response confirmation (delete this bullet)• – Validity of imaging as a measure of efficacy (delete

this bullet)


Technical Considerations

• Same imaging technique at every time point

• Measurements in the Axial plane

• Acquisition 3-mm, skip 0-mm T1-weighted C+ images improve resolution – Increase acquisition time from 3 minutes to 5–6

minutes improved resolution is a great benefit

• Postcontrast axial – Same Gd dose each time– Standardized time interval post Gd (>5min <

10min)

Move to follow slide 15.


Measurement Techniques

Two major approaches for evaluation of contrast-enhancing tumor size:

1. Diameter-based measurement on – single-axial section containing largest

diameter

2. Computer-assisted volumetric

analysis– all sections containing tumor

– Slide 16 and 17: Need to add diameter based measurement examples, goal here is for site measurements to hopefully be in line with IRF measurements (may want to take off volumetrics, not assessable at site level)


A) homogeneously enhancing >10 mm in diameter ideal for serial measurement by RECIST or 1D 0rMacdonald or 2D, and volumetric.

B) predominantly necrotic ideal for volumetric measurement (because the enhancing and nonenhancing components can be segmented)

C) too small in diameter (8 mm) for accurate serial measurement and should be followed as a nonmeasurable lesion

http://www.ajnr.org/content/vol29/issue3/images/large/zj40050809630001.jpeg


Macdonald Criteria (2D)

• To date, most trials for GBM use the WHO-based “Macdonald criteria”– Measure

maximal enhancing tumor diameter on single axial Post C T1 image, and

largest perpendicular diameter same image– Calculate product of the 2 diameters– Sum Measurements from multiple lesions

Macdonald DR Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8: 1277-1280

http://jco.ascopubs.org/current.dtl


Limitations of Macdonald• Key Limitations

– Necrotic portions of lesions– Assumption contrast enhanced tissue =

tumor enhancement nonspecific

o reflects disrupted blood-brain barriero induced by of nontumoral processes

» inflammation,

» seizure activity, » postsurgical changes, and » radiation necrosis.

enhancement influencedo changes in corticosteroid dose and o radiologic technique

– Changes in the enhancing area cannot be equated with changes in tumor size or tumor growth/activity


Copyright restrictions may apply.

Brandes, A. A. et al. NEURO ONCOL 2008 10:361-367; doi:10.1215/15228517-2008-008

Clinical course of pseudoprogression in a 65-year-old patient with glioblastoma multiforme


Journal of Clinical Oncology, Vol 28, No 11 (April 10), 2010: pp. 1963-1972

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Patrick Y. Wen, David R. Macdonald, David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen, Evanthia

Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman, Christina Tsien, Tom Mikkelsen, Eric T.

Wong, Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn, Michael A. Vogelbaum, Martin J. van den Bent,

Susan M. Chang

http://jco.ascopubs.org/current.dtl


RANO Criteria: Same Limitations

• In RANO, increasing areas of FLAIR signal abnormality without corresponding changes in enhancement can be used to establish progressive disease.

• This is not optimal, however, as increasing FLAIR signal from radiation gliosis and other treatment effects are not necessarily associated with progression of non-enhancing tumor.

• Indeed the RANO group concluded that “although it would be preferable to have an objective measure of progressive non-enhancing recurrent disease similar to contrast-enhancing disease, the RANO working group felt that this was not possible at present given the limitations of current technology.”

T1 Post Contrast T1 Post Contrast

Slide 46, 47, 48: Move to response criteria portion of presentation


Multicentric Lesions• Approximately one third of malignant

gliomas are multicentric at the time of diagnosis, and in half of these cases, there are discrete foci of enhancement.

• The approach in this situation is to measure and record each separately enhancing lesion that meets inclusion criteria and sum the measurements.

Move to response criteria portion of presentation


Nonmeasurable Lesions

• Important in Clinical Trials – Tumor progression may occur in these

sites

• Nonmeasurable lesion includes:– Foci of enhancement <8mm– Region of T2-weighted hyperintensity

surrounding enhancing tumor – Discrete foci of non-enhancing T2-

weighted hyperintensity (multicentric tumor)

– Hemorrhagic or predominantly cystic or necrotic lesions

– Leptomeningeal tumor Move to lesion selection portion of the presentation.


2nd f/u: remote non-enhancing disease

Example of Conversion from Enhancing to Non-enhancing Tumor Following Avastin

Treatment

Baseline: avid enhancement

T1 Post Contrast

T2

1st f/u: little enhancement


Example of Conversion from Enhancing to Non-enhancing Tumor Following Avastin

Treatment

Baseline: avid enhancement

1st f/u: little enhancement

T1 Post Contrast

2nd f/u: remote non-enhancing disease

T2

Response?

Progression?


Example of Faintly Enhancing Tumor (Post Treatment)

FLAIR FLAIR

Faintly enhancing tumor Faintly enhancing tumor

T1 Post Contrast

: Can you add measurement caliper placements on these images (to be consistent with IRF measurements)


Example of Conversion from Enhancing to Non-enhancing Tumor Following Treatment

Baseline: avid enhancement 1st Follow-up: only tiny nodular peripheral enhancement

T1 Post ContrastT1 Post ContrastT1 Post Contrast

2nd Follow-up: no enhancement. New distant disease (see next slide)


Same Case: Development of distant non-enhancing tumor. Example of conversion from local to diffuse

disease following treatment.

Baseline: enhancing tumorand vasogenic edema

1st Follow-up: much lessedema. Non-enhancingtumor remains.

T2T2T2

2nd Follow-up: interval development of non-enhancing, ill-defined, tumor > 3cm from primary site, thus scored as diffuse progression


Example of Multifocal Disease

T2

Two sites of enhancing tumorGreater than 3 cm from primary site, separated by normal brain

T1 Post Contrast


Same Patient: Conversion from Multifocal to Diffuse Disease Following Treatment

T2

Distant non-enhancing tumorwith ill-defined margins, enhancement atprimary site goes away.

Non-enhancing tumor – no cortical ribbonVasogenic Edema – cortical ribbon seen

T1 Post Contrast


Another Example of Multifocal Disease

T1 Post Contrast FLAIR

Multifocal, enhancing tumor


Local Recurrence

Single focus of enhancing tumor


5-12-05

GBM – Distant Non-enhancing Tumor

12-5-05

Delete


Corticosteroid-induced Magnetic Resonance Imaging Changes

Post Steroids – 90% patients had decreased

enhancement or T2 signal 30% patients had 25%+ reduction in

enhancing tumor 50% had 25%+ reduction in edema

– Maximal effect was achieved at 2 weeks Thus 2 weeks stable dose steroid

recommended before baseline imaging.

J Clin Oncol. 1994 Sep;12(9):1886-9.

How to add steroid on study to maintain image accuracy (ie, contrast intolerant subjects what steroid prescribed previous to next MRI)


Initial scan 2 weeks after steroid tx

Edema – often only temporary reduction in edema

T1 Post Contrast

Steroids: Example of Effect on Edema and Enhancement


Computer-Aided Volumetric Methods

• Segmentation Algorithm generates border between the enhancing and non-enhancing

regions on all adjacent axial sections

• Neuroradiologist – Reviews contours– Edits contour if needed

• Program Calculates– enhancing volume,– Non-enhancing volume (i.e., the centrally necrotic

or cystic portion)– Total or combined lesion volume in cubic– Bi dimensional measurements


RECIST (1D)3 Macdonald (2D)4

Volumetric Extrapolated from RECIST*,

Volumetric Extrapolated from

Macdonald*,

CR Resolution of all enhancing tumor; confirm at 4 weeks

Resolution of all enhancing tumor; confirm at 4 weeks

Resolution of all enhancing tumor; confirm at 4 weeks

Resolution of all enhancing tumor; confirm

at 4 weeks

PR 30% decrease in sum of maximal diameters; confirm at 4 weeks

50% decrease in product of 2 orthogonal diameters;

confirm at 4 weeks

66% decrease in volume; confirm at 4 weeks

65% decrease in volume; confirm at 4 weeks

SD All others All others All others All others

PD|| 20% increase in sum of maximal diameters; confirm at 4 weeks

25% increase in product of orthogonal diameters;

confirm at 4 weeks

73% increase in volume; confirm at 4 weeks

40% increase in volume; confirm at 4 weeks

Comment Single longest diameter of the lesion or sum of longest diameters of multiple measurable

lesions (see text)

Product of orthogonal diameters on section with largest tumor area; sum of

products if multiple measurable lesions

Computer-assisted volumetrics using a

perimeter methodology; sum of volumes if multiple

measurable lesions

Use of these values would be equally stringent for

PR comparing RECIST and Macdonald criteria but

would be more stringent for PD compared with

RECIST but comparable with Macdonald criteria

Move to response criteria portion of presentation


Dynamic Contrast Enhanced (DCE)-MRIPhysics

• Gadolinium causes a change in the longitudinal relaxivity (R1 = 1/T1) of surrounding water proportional to concentration

• Dynamic Contrast Enhanced MRI uses gadolinium-based contrast agents as a tracer for pharmacokinetic analysis by collecting dynamic T1-weighted images during a bolus

Plasma Cp(t)

RBC

Vein, Cv(t)

TissueEESCe(t)Ve

Ktrans

kep

1-Hct

Artery, Ca(t)

Two-CompartmentTofts Model(most common)


Dynamic Contrast Enhanced (DCE)-MRIUtility in Glioblastoma

• Ktrans ~ 0 in normal brain tissue because of the blood brain barrier (BBB)

• Ktrans in Glioblastoma due to BBB compromise during creation of new (abnormal) blood vessels (angiogenesis)



• Voxel-wise Ktrans Calculations = Permeability Maps



• Voxel-wise Ktrans Calculations = Permeability Maps– Biomarker for anti-angiogenic drugs targeting abnormal blood

vessels

Early Treatment Failure




vessels– Widely accepted in clinical trials of other cancers

O’Connor, Br J Cancer 2007




vessels– Widely accepted in clinical trials of other cancers– Voxel-wise changes in Ktrans shows spatially heterogeneous

responseParametric Response Maps (PRM)


Dynamic Contrast Enhanced (DCE)-MRILimitations/Challenges

• Measurement Error in pre-contrast T1• Crucial for accurate concentration estimation• Need accurate flip angle measurements• QC:

• T1 fit (R2 > 0.7, P < 0.05)• T1 in Normal Tissues

1.5T: Breger, 1989; Steen, 1994; Whittall, 1997; Haacke, 19993.0T: Wansapura, 1999; Helms, 2008



• Measurement Error in pre-contrast T1• Crucial for accurate concentration estimation• Need accurate flip angle measurements

• Issues with Repeatability• Random error, biological variation• Confidence depends on

• Choice of model (2-compartment, 3-compartment, etc)

• ROI definition• AIF determination







• QC: Average of both ICAs







• Median Change in Ktrans > 40% Reflects True Response








• Failure to Detect Response• Sampling at wrong time point during treatment• Averaging effects over ROI/VOI








• Failure to Detect Response• Sampling at wrong time point during treatment• Averaging effects over ROI/VOI

• Solution: Histogram and Voxel-wise analyses


Dynamic Susceptibility Contrast MRIPhysics

• Gadolinium also has a transient effect on the magnetic susceptibility on blood and tissue water in high concentrations

Magnetic Susceptibility


Dynamic Susceptibility Contrast (DSC) MRIPhysics


• Gadolinium causes signal loss on T2*-weighted images

Pre-Injection During Bolus Passage

Dark = Vessels


Dynamic Susceptibility Contrast (DSC) MRIPhysics


• Gadolinium causes signal loss on T2*-weighted images

• Area under relaxivity (R2* or R2) vs. time is proportional to blood volume (assuming no leakage)

Voxel Signal vs. Time

Dynamic T2* Image Acquisition

R2* vs. Time

Cerebral Blood Volume(CBV)


Dynamic Susceptibility Contrast (DSC) MRIUtility in Glioblastoma

• Glioblastoma has elevated CBV due to angiogenesis

Post-Contrast T1-Weighted Image DSC-MRI Estimate of CBV

Normal Vessels

AbnormalVascularity



• Change in CBV is associated with successful treatment



• Voxel-wise changes for spatially heterogeneous response

Pre-Tx Post-Tx Pre-Tx Post-Tx

Responder Non-Responder


Dynamic Susceptibility Contrast (DSC) MRILimitations/Challenges

• CBV measurements are dependent on an intact BBB– NOT the case in Glioblastoma

Boxerman, 2006



• CBV measurements are dependent on an intact BBB– NOT the case in Glioblastoma– Solution: Pre-load + Post-hoc Leakage Correction

(not standard in most commercial software)

Boxerman, 2006





• CBV measurements are “relative” – Typical solution is to “normalize” to contralateral tissue– Our Solution: Image Intensity “Standardization” (piecewise

histogram)





• CBV measurements are “relative” – Typical solution is to “normalize” to contralateral tissue– Our Solution: Image Intensity “Standardization” (piecewise

histogram)

• Prone to susceptibility artifacts if patient has surgical hardware

• Must have a good bolus (AIF)– If tight bolus of contrast agent is not achievable, data will be

poor


[18F]-fluorodeoxyglucose (FDG) PETPhysics

• 18F-FDG is has uptake like glucose, but is trapped inside cells during metabolism

• PET data typically collected at a single (static) time point 60 min after injection (collected for 30 min)

Miele, 2008


[18F]-fluorodeoxyglucose (FDG) PETUtility in Glioblastoma

• High energy demand = FDG uptake• Quantified using Standard Uptake Values (SUV)


[18F]-fluorodeoxyglucose (FDG) PETUtility in Glioblastoma

• Voxel-wise changes in PET show heterogeneous response [18F]-FDOPA shown below


[18F]-fluorodeoxyglucose (FDG) PETLimitations/Challenges

• High uptake in normal cortex


Multiparametric Imaging

• Combining voxel-wise changes in Perfusion & Diffusion

3 Mo. Post-Tx 6 Mo. Post-Tx 12 Mo. Post-Tx


Multiparametric Imaging

• Combining Perfusion, Diffusion, & PET

whitney pope, md, phd director of neuro core, medqia director of brain tumor imaging, assistant...

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