Presentation is loading. Please wait.

Presentation is loading. Please wait.

Whitney Pope, MD, PhD Director of Neuro Core, MedQIA Director of Brain Tumor Imaging, Assistant Professor of Neuroradiology, University of California,

Similar presentations


Presentation on theme: "Whitney Pope, MD, PhD Director of Neuro Core, MedQIA Director of Brain Tumor Imaging, Assistant Professor of Neuroradiology, University of California,"— Presentation transcript:

1 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 3 rd, 2010 Scientific Aspect of GB Imaging

2 XL Investigator Meeting - Confidential 2 Outline 1,

3 XL Investigator Meeting - Confidential 3 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 T1 Bright on T2 Almost always enhances +/- Necrotic Brain slice Pathology T1 + contrastT2

4 XL Investigator Meeting - Confidential 4 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

5 XL Investigator Meeting - Confidential 5 Examples of “Typical” GBM Enhancing, Necrotic Tumor T1 Post ContrastT2

6 XL Investigator Meeting - Confidential 6 Example of Enhancing versus Non-Enhancing Tumor FLAIR T2 Non-enhancing and enhancing tumorNon-enhancing tumor T1 Post Contrast Enhancing tumor Vasogenic edema

7 XL Investigator Meeting - Confidential 7 FLAIR Can Improve Tumor Visualization insert slide to encourage dwi T2 FLAIR Tumor Insert next slide a dwi slide to encourage this is done

8 XL Investigator Meeting - Confidential 8 T2 versus FLAIR: More examples Tumor and edema Tumor only T2 FLAIR

9 XL Investigator Meeting - Confidential 9 Examples of non contrast enhancing tumor GBM Non-enhancing GBM showing biopsy site Intraventricular GBM with enhancing and non-enhancing tumor GBM Imaging

10 XL Investigator Meeting - Confidential 10 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 action o Pilot efficacy – Phase III  Primary goal overall survival  Imaging o used at clinical sites to manage patients o Secondary endpoints

11 XL Investigator Meeting - Confidential 11 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

12 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 14 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)

15 XL Investigator Meeting - Confidential 15 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

16 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 17 Limitations of Macdonald Key Limitations – Necrotic portions of lesions – Assumption contrast enhanced tissue = tumor  enhancement nonspecific o reflects disrupted blood-brain barrier o induced by of nontumoral processes » inflammation, » seizure activity, » postsurgical changes, and » radiation necrosis.  enhancement influenced o 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

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

19 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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 Slide 46, 47, 48: Move to response criteria portion of presentation

21 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 23 2 nd 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 1 st f/u: little enhancement

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

25 XL Investigator Meeting - Confidential 25 Example of Faintly Enhancing Tumor (Post Treatment) FLAIRFLAIR Faintly enhancing tumor T1 Post Contrast : Can you add measurement caliper placements on these images (to be consistent with IRF measurements)

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

27 XL Investigator Meeting - Confidential 27 Same Case: Development of distant non-enhancing tumor. Example of conversion from local to diffuse disease following treatment. Baseline: enhancing tumor and vasogenic edema 1 st Follow-up: much less edema. Non-enhancing tumor remains. T2T2 T2 2 nd Follow-up: interval development of non- enhancing, ill-defined, tumor > 3cm from primary site, thus scored as diffuse progression

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

29 XL Investigator Meeting - Confidential 29 Same Patient: Conversion from Multifocal to Diffuse Disease Following Treatment 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 T1 Post Contrast

30 XL Investigator Meeting - Confidential 30 Another Example of Multifocal Disease T1 Post Contrast FLAIR Multifocal, enhancing tumor

31 XL Investigator Meeting - Confidential 31 Local Recurrence Single focus of enhancing tumor

32 XL Investigator Meeting - Confidential GBM – Distant Non-enhancing Tumor Delete

33 XL Investigator Meeting - Confidential 33 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 Sep;12(9): How to add steroid on study to maintain image accuracy (ie, contrast intolerant subjects what steroid prescribed previous to next MRI)

34 XL Investigator Meeting - Confidential 34 Initial scan2 weeks after steroid tx Edema – often only temporary reduction in edema T1 Post Contrast Steroids: Example of Effect on Edema and Enhancement

35 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 36 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 Move to response criteria portion of presentation

37 XL Investigator Meeting - Confidential 37 Dynamic Contrast Enhanced (DCE)-MRI Physics Gadolinium causes a change in the longitudinal relaxivity (R 1 = 1/T 1 ) 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 C p (t) RBC Vein, C v (t) Tissue EES C e (t) V e K trans k ep 1-Hct Artery, C a (t) Two-Compartment Tofts Model (most common)

38 XL Investigator Meeting - Confidential 38 Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma K trans ~ 0 in normal brain tissue because of the blood brain barrier (BBB) K trans  in Glioblastoma due to BBB compromise during creation of new (abnormal) blood vessels (angiogenesis)

39 XL Investigator Meeting - Confidential 39 Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma Voxel-wise K trans Calculations = Permeability Maps

40 XL Investigator Meeting - Confidential 40 Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma Voxel-wise K trans Calculations = Permeability Maps – Biomarker for anti-angiogenic drugs targeting abnormal blood vessels Early Treatment Failure

41 XL Investigator Meeting - Confidential 41 Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma Voxel-wise K trans 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 XL Investigator Meeting - Confidential 42 Dynamic Contrast Enhanced (DCE)-MRI Utility in Glioblastoma Voxel-wise K trans Calculations = Permeability Maps – Biomarker for anti-angiogenic drugs targeting abnormal blood vessels – Widely accepted in clinical trials of other cancers – Voxel-wise changes in K trans shows spatially heterogeneous response Parametric Response Maps (PRM)

43 XL Investigator Meeting - Confidential 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 (R 2 > 0.7, P < 0.05) T1 in Normal Tissues 1.5T: Breger, 1989; Steen, 1994; Whittall, 1997; Haacke, T: Wansapura, 1999; Helms, 2008

44 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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  K trans > 40% Reflects True Response

47 XL Investigator Meeting - Confidential 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  K trans > 40% Reflects True Response Failure to Detect Response Sampling at wrong time point during treatment Averaging effects over ROI/VOI

48 XL Investigator Meeting - Confidential 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  K trans > 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 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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-InjectionDuring Bolus Passage Dark = Vessels

51 XL Investigator Meeting - Confidential 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) Voxel Signal vs. Time Dynamic T2* Image Acquisition R2* vs. Time Cerebral Blood Volume (CBV)

52 XL Investigator Meeting - Confidential 52 Dynamic Susceptibility Contrast (DSC) MRI Utility in Glioblastoma Glioblastoma has elevated CBV due to angiogenesis Post-Contrast T1-Weighted ImageDSC-MRI Estimate of CBV Normal Vessels Abnormal Vascularity

53 XL Investigator Meeting - Confidential 53 Dynamic Susceptibility Contrast (DSC) MRI Utility in Glioblastoma Change in CBV is associated with successful treatment

54 XL Investigator Meeting - Confidential 54 Dynamic Susceptibility Contrast (DSC) MRI Utility in Glioblastoma Voxel-wise changes for spatially heterogeneous response Pre-TxPost-TxPre-TxPost-Tx ResponderNon-Responder

55 XL Investigator Meeting - Confidential 55 Dynamic Susceptibility Contrast (DSC) MRI Limitations/Challenges CBV measurements are dependent on an intact BBB – NOT the case in Glioblastoma Boxerman, 2006

56 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 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 XL Investigator Meeting - Confidential 59 [ 18 F]-fluorodeoxyglucose (FDG) PET Physics 18 F-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 XL Investigator Meeting - Confidential 60 [ 18 F]-fluorodeoxyglucose (FDG) PET Utility in Glioblastoma High energy demand =  FDG uptake Quantified using Standard Uptake Values (SUV)

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

62 XL Investigator Meeting - Confidential 62 [ 18 F]-fluorodeoxyglucose (FDG) PET Limitations/Challenges High uptake in normal cortex

63 XL Investigator Meeting - Confidential 63 Multiparametric Imaging Combining voxel-wise changes in Perfusion & Diffusion 3 Mo. Post-Tx6 Mo. Post-Tx12 Mo. Post-Tx

64 XL Investigator Meeting - Confidential 64 Multiparametric Imaging Combining Perfusion, Diffusion, & PET


Download ppt "Whitney Pope, MD, PhD Director of Neuro Core, MedQIA Director of Brain Tumor Imaging, Assistant Professor of Neuroradiology, University of California,"

Similar presentations


Ads by Google