1. Scientific Aspect of GB Imaging
Whitney Pope, MD, PhD
Director of Neuro Core, MedQIA
Director of Brain Tumor Imaging,
Assistant Professor of Neuroradiology,
University of California, Los Angeles
XL Investigator Meeting
June 3rd, 2010

2. Outline 1,

3. Astrocytoma: grade IV - GBM
T1 + contrast T2
At UCLA
GBM: 2 year survival - 24%
5 year survival – 0%
If grade III has imaging evidence of
necrosis: same survival curve as GBM
Low on T1
Bright on T2
Almost always enhances
+/- Necrotic
Brain slice
Pathology

4. Appearance of GBM on MRI
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) A B C D

5. Examples of “Typical” GBM
Enhancing, Necrotic Tumor
T1 Post Contrast T2

6. Example of Enhancing versus Non-Enhancing Tumor
Vasogenic edema
T1 Post Contrast T2
FLAIR
Non-enhancing and enhancing tumor
Non-enhancing tumor
Enhancing tumor

7. FLAIR Can Improve Tumor Visualization insert slide to encourage dwi
Insert next slide a dwi slide to encourage this is done
FLAIR T2
Tumor

8. T2 versus FLAIR: More examples
Tumor only
Tumor and edema T2
FLAIR

9. Examples of non contrast enhancing tumor GBM
Non-enhancing GBM showing biopsy site
GBM Imaging
Intraventricular GBM with enhancing and non-enhancing tumor

10. Role of Imaging in Clinical Trials
Imaging plays an important role in all Clinical trials
Phase I
Primary goal tolerated dose
Imaging exploratory
Mechanism of action
Pilot efficacy
Phase III
Primary goal overall survival
Imaging
used at clinical sites to manage patients
Secondary endpoints

11. Challenges in GBM assessment
Phase II
goal therapeutic effect
Imaging is a primary endpoint
( 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

12. 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)

13. 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.

14. Measurement Techniques
Two major approaches for evaluation of contrast-enhancing tumor size:
Diameter-based measurement on
single-axial section containing largest diameter
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)

15. homogeneously enhancing >10 mm in diameter ideal for serial measurement by RECIST or 1D 0rMacdonald or 2D, and volumetric.
predominantly necrotic ideal for volumetric measurement (because the enhancing and nonenhancing components can be segmented)
too small in diameter (8 mm) for accurate serial measurement and should be followed as a nonmeasurable lesion

16. 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:

17. Limitations of Macdonald
Key Limitations
Necrotic portions of lesions
Assumption contrast enhanced tissue = tumor
enhancement nonspecific
reflects disrupted blood-brain barrier
induced by of nontumoral processes
inflammation,
seizure activity,
postsurgical changes, and
radiation necrosis.
enhancement influenced
changes in corticosteroid dose and
radiologic technique
Changes in the enhancing area cannot be equated with changes in tumor size or tumor growth/activity

18. Clinical course of pseudoprogression in a 65-year-old patient with glioblastoma multiforme
Brandes, A. A. et al. NEURO ONCOL : ; doi: /
Copyright restrictions may apply.

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

20. 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

21. 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

22. 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.

23. Example of Conversion from Enhancing to Non-enhancing Tumor Following Avastin Treatment
1st f/u: little enhancement
2nd f/u: remote non-enhancing disease
T1 Post Contrast
Baseline: avid enhancement T2

24. Example of Conversion from Enhancing to Non-enhancing Tumor Following Avastin Treatment
T1 Post Contrast
Response?
2nd f/u: remote non-enhancing disease
Baseline: avid enhancement
1st f/u: little enhancement
Progression? T2

25. Example of Faintly Enhancing Tumor (Post Treatment)
FLAIR
FLAIR
T1 Post Contrast
:  Can you add measurement caliper placements on these images (to be consistent with IRF measurements)
Faintly enhancing tumor
Faintly enhancing tumor

26. Example of Conversion from Enhancing to Non-enhancing Tumor Following Treatment
T1 Post Contrast
T1 Post Contrast
T1 Post Contrast
1st Follow-up: only tiny nodular peripheral enhancement
2nd Follow-up: no enhancement. New distant disease (see next slide)
Baseline: avid enhancement

27. Same Case: Development of distant non-enhancing tumor
Same Case: Development of distant non-enhancing tumor. Example of conversion from local to diffuse disease following treatment. T2 T2 T2
2nd Follow-up: interval
development of non-
enhancing, ill-defined, tumor > 3cm from primary site, thus scored as diffuse progression
1st Follow-up: much less
edema. Non-enhancing
tumor remains.
Baseline: enhancing tumor
and vasogenic edema

28. Example of Multifocal Disease
T1 Post Contrast T2
Greater than 3 cm from primary site,
separated by normal brain
Two sites of enhancing tumor

29. Same Patient: Conversion from Multifocal to Diffuse Disease Following Treatment
T1 Post Contrast T2
Distant non-enhancing tumor
with ill-defined margins, enhancement at
primary site goes away.
Non-enhancing tumor – no cortical ribbon
Vasogenic Edema – cortical ribbon seen

30. Another Example of Multifocal Disease
FLAIR
T1 Post Contrast
Multifocal, enhancing tumor

31. Local Recurrence
Single focus of enhancing tumor

32. GBM – Distant Non-enhancing Tumor
Delete

33. Corticosteroid-induced Magnetic Resonance Imaging Changes
How to add steroid on study to maintain image accuracy (ie, contrast intolerant subjects what steroid prescribed previous to next MRI)
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 Sep;12(9):

34. Steroids: Example of Effect on Edema and Enhancement
T1 Post Contrast
Initial scan
2 weeks after steroid tx
Edema – often only temporary reduction in edema

35. 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

36. Move to response criteria portion of presentation
RECIST (1D)3
Macdonald (2D)4
Volumetric Extrapolated from RECIST*,
Volumetric Extrapolated from Macdonald*, CR
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
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

37. Dynamic Contrast Enhanced (DCE)-MRI Physics
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
Artery, Ca(t)
Tissue
EES
Ce(t) Ve
Plasma
Cp(t)
RBC
Ktrans
Two-Compartment
Tofts Model
(most common)
1-Hct
kep
Vein, Cv(t)

38. Dynamic Contrast Enhanced (DCE)-MRI Utility 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)

39. Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma
Voxel-wise Ktrans Calculations = Permeability Maps

40. Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma
Voxel-wise Ktrans Calculations = Permeability Maps
Biomarker for anti-angiogenic drugs targeting abnormal blood vessels
Early Treatment Failure

41. Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma
Voxel-wise Ktrans Calculations = Permeability Maps
Biomarker for anti-angiogenic drugs targeting abnormal blood vessels
Widely accepted in clinical trials of other cancers
O’Connor, Br J Cancer 2007

42. Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma
Voxel-wise Ktrans Calculations = Permeability Maps
Biomarker for anti-angiogenic drugs targeting abnormal blood vessels
Widely accepted in clinical trials of other cancers
Voxel-wise changes in Ktrans shows spatially heterogeneous response
Parametric Response Maps (PRM)

43. Dynamic Contrast Enhanced (DCE)-MRI Limitations/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, 1999
3.0T: Wansapura, 1999; Helms, 2008

44. Dynamic Contrast Enhanced (DCE)-MRI Limitations/Challenges
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

45. Dynamic Contrast Enhanced (DCE)-MRI Limitations/Challenges
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

46. Dynamic Contrast Enhanced (DCE)-MRI Limitations/Challenges
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
Median Change in Ktrans > 40% Reflects True Response

47. Dynamic Contrast Enhanced (DCE)-MRI Limitations/Challenges
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
Median Change in Ktrans > 40% Reflects True Response
Failure to Detect Response
Sampling at wrong time point during treatment
Averaging effects over ROI/VOI

48. Dynamic Contrast Enhanced (DCE)-MRI Limitations/Challenges
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
Median Change in Ktrans > 40% Reflects True Response
Failure to Detect Response
Sampling at wrong time point during treatment
Averaging effects over ROI/VOI
Solution: Histogram and Voxel-wise analyses

49. Dynamic Susceptibility Contrast MRI Physics
Gadolinium also has a transient effect on the magnetic susceptibility on blood and tissue water in high concentrations
Magnetic
Susceptibility

50. Dynamic Susceptibility Contrast (DSC) MRI Physics
Gadolinium also has a transient effect on the magnetic susceptibility on blood and tissue water in high concentrations
Gadolinium causes signal loss on T2*-weighted images
Pre-Injection
During Bolus Passage
Dark = Vessels

51. Dynamic Susceptibility Contrast (DSC) MRI Physics
Gadolinium also has a transient effect on the magnetic susceptibility on blood and tissue water in high concentrations
Gadolinium causes signal loss on T2*-weighted images
Area under relaxivity (R2* or R2) vs. time is proportional to blood volume (assuming no leakage)
Dynamic T2*
Image Acquisition
Cerebral Blood Volume
(CBV)
Voxel Signal vs. Time
R2* vs. Time

52. Dynamic Susceptibility Contrast (DSC) MRI Utility in Glioblastoma
Glioblastoma has elevated CBV due to angiogenesis
Post-Contrast T1-Weighted Image
DSC-MRI Estimate of CBV
Normal Vessels
Abnormal
Vascularity

53. Dynamic Susceptibility Contrast (DSC) MRI Utility in Glioblastoma
Change in CBV is associated with successful treatment

54. Dynamic Susceptibility Contrast (DSC) MRI Utility in Glioblastoma
Voxel-wise changes for spatially heterogeneous response
Responder
Non-Responder
Pre-Tx
Post-Tx
Pre-Tx
Post-Tx

55. Dynamic Susceptibility Contrast (DSC) MRI Limitations/Challenges
CBV measurements are dependent on an intact BBB
NOT the case in Glioblastoma
Boxerman, 2006

56. Dynamic Susceptibility Contrast (DSC) MRI Limitations/Challenges
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

57. Dynamic Susceptibility Contrast (DSC) MRI Limitations/Challenges
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)
CBV measurements are “relative”
Typical solution is to “normalize” to contralateral tissue
Our Solution: Image Intensity “Standardization” (piecewise histogram)

58. Dynamic Susceptibility Contrast (DSC) MRI Limitations/Challenges
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)
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

59. [18F]-fluorodeoxyglucose (FDG) PET Physics
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

60. [18F]-fluorodeoxyglucose (FDG) PET Utility in Glioblastoma
High energy demand =  FDG uptake
Quantified using Standard Uptake Values (SUV)

61. [18F]-fluorodeoxyglucose (FDG) PET Utility in Glioblastoma
Voxel-wise changes in PET show heterogeneous response
[18F]-FDOPA shown below

62. [18F]-fluorodeoxyglucose (FDG) PET Limitations/Challenges
High uptake in normal cortex

63. Multiparametric Imaging
Combining voxel-wise changes in Perfusion & Diffusion
3 Mo. Post-Tx
6 Mo. Post-Tx
12 Mo. Post-Tx

64. Multiparametric Imaging
Combining Perfusion, Diffusion, & PET