1. Methods to Differentiate Radiation Induced Necrosis and Recurrent Disease in Gliomas Lars Ewell University of Arizona Medical Center Department of Radiation Oncology MRI Research Group 2/2/07

2. 2 Methods to Differentiate Radiation Induced Necrosis and Recurrent Disease in Gliomas I.Introduction: The Problem II.Radiation Damage: Brain vs. Tumor III.Similarities/Differences IV.MRS: Metabolite Ratios V.DWMRI: ADC VI.ABRC Grant VII.Conclusion

3. Radiation Induced Necrosis Radiation is one of the few proven currently known methods to increase survival and quality of life for glioma (brain tumor) patients. Radiation dose has been correlated with recurrence. Too much radiation can kill normal brain tissue. 3

4. Radiation Dose  [dose] = Energy/Mass and the SI unit of dose = Gray = Gy = 1J/Kg. Lethal dose is ~4Gy given to the whole body in ~ seconds. Typical Rx dose for a glioma is 60Gy given in 30 Fx (2Gy/Fx) over 6 weeks. Diagnostic dose (CAT Scan) ~10cGy. Dose  with the energy imparted by ionizing radiation to material of mass. 4

5. Radiation Damage: Cell Survival The ratio  has units of dose, and is used to determine tissue radiation reaction. 5 10 0 10 -1 10 -2 Surviving Fraction Radiation Dose (Gy) 4 812 The ‘linear – quadratic’ model of cell survival, w/ S the surviving fraction, D the dose and  constants.

6. Radiation Damage: Early - Late The ratio  has been correlated with response time for radiation damage to manifest. For brain and/or spinal cord,  ~ 2Gy indicating a late radiation response (months to years). For tumor,  ~ 10 Gy indicating an early radiation response (weeks to months). 6

7. RIN/Recurrent Disease T1 weighted contrast enhanced MRI taken 16 months after completion of radiotherapy (left). Same MRI taken 2 months, 15 days later. Biopsy later revealed no evidence of recurrent tumor. 7 Kumar et al., Radiology, 217, 2, November 2000.

8. RIN/Recurrent Disease: Comparison 1.‘Enhancing lesion’ on MRI. 2.Origin at or near primary site. 3.Growth over time. 8 1.Additional radiation can benefit recurrent disease. 2.Additional radiation detrimental to RIN. Similarities: Differences:

9. DWMRI to Distinguish RIN and Recurrent Disease Since RIN may have same characteristics as successfully treated tumor, one may think that using DWMRI could differentiate RIN from recurrent disease. However, initial studies show little value in using DWMRI to differentiate RIN and recurrent disease. Limited resolution of DWMRI one problem. Radial Fast Spin Echo (RFSE) promises better DWMRI resolution. 9

10. Magnetic Resonance Spectroscopy MRS, also called Chemical Shift Imaging (CSI), gets signal from shift in resonance due to surrounding chemical environment. Using MRS, the ratio of brain metabolites such as Choline (Cho), Creatine (Cr) and N- Acetylaspartate (NAA) can be measured. These ratios have been shown to have power to discriminate RIN and recurrent disease. 10

11. MRS Metabolites Cho is a neurotransmitter and is increased in tumors. Correlated with high cellular density. NAA is a metabolite found in neurons, and is decreased in tumors. Cr is a brain metabolite and is also decreased in tumors. 11

12. 2D CSI scans given to seven patients. 16cm FOV, 16x16 and slice thickness of 10- 20mm. 1 average, scan time of 4 min., 20sec. Absence of tumor confirmed by biopsy in two patients. 12 * * Weybright et al., Neuroradiology (2004) 46: 541–549 * MRS Metabolite Ratios

13. Magnetic Resonance Spectroscopy 13 Cho Cr NAA

14. MRS ‘Quick and Dirty’ 2D multi-voxel scans taken 1/25/07 – pre and post Gd. 3:18 with 2 NEX. 3x3cm voxels, 1cm thick. Disease visible in voxel #2. 14

15. MRS: Normal vs. Disease 15 Voxel # 7 - NormalVoxel # 2 - Disease

16. MRS: Pre vs. Post Gd 16 Pre GdPost Gd

17. Magnetic Resonance Spectroscopy Although MRS has been shown to have discriminating power, there are two problems associated with it: 1) Low resolution. 2) Long scan time. Imaging protocol will join MRS with RFSE DWMRI to create synergistic combination. 17

18. Arizona Biomedical Research Commission Grant Awarded: Diffusion Weighted MRI and Magnetic Resonance Spectroscopy to Differentiate Radiation Necrosis and Recurrent Disease in Gilomas (PI LAE). Enroll 60 patients diagnosed with a glioma (metastatic or primary) and follow longitudinally. 18

19. Imaging Protocol Patients eligible to enroll if they have a reasonable risk of suffering from RIN. Published data indicate that patients receiving a dose of  60Gy in 30 Fx have between a 5 and 24% chance of developing RIN. Hypo-fractionation and Stereotactic Radio- Surgery (SRS) are also forms of radiation Tx. 19

20. Imaging Protocol: Enrollment Criteria Biological Equivalent Dose (BED) used to determine enrollment criteria for hypo- fractionation and SRS. 20 BED = nd(1 + ) with n the number of fractions, d the dose,  and  the linear quadratic constants. 5 x 6Gy required for hypo - fractionation, 21Gy for SRS.

21. 21 Imaging Protocol: Enrollment Criteria Radiation TypeNumber of Fractions Minimum Radiation (Gy) SRS121 Hypo-fraction530 Normal Fraction3060 Re-treatmentvaries

22. 22 Imaging Protocol: Imaging Sequence Time from End of Radiotherapy (days) Scans PerformedComments -5CT, MRI, DWMRI, MRSBaseline scans. Used to plan radiotherapy. CT and MRI registered using Brainscan. 30MRI, DWMRI, MRSFirst scan for comparison. 90MRI, DWMRI, MRSSecond scan for comparison. Potential radiation necrosis. Check ADC W for change.

23. 23 Imaging Protocol VOI centered at center of resection cavity. 2D Multi-voxel CSI with 1cm slice thickness. 7x7cm. Three slices, ~8:30 for each slice, one centered on lesion and one superior and inferior. MRS will take majority of time.

24. 24 Imaging Protocol Current ‘Gold Standard’ for confirming glioma vs. RIN is pathologic examination of biopsy. We expect that ~50% of enrolled patients will undergo biopsy at some point. Vector Vision should locate biopsy location to within ~2mm. Biopsy MRI registered with protocol MRI using Brainscan software.

25. 25 Imaging Protocol Approved by SRC 11/14/06. Third submission to IRB will take place early next week. Expect approval shortly thereafter – 2/13/07 Patient enrollment thereafter.

26. Conclusion DWMRI and MRS are non-invasive forms of medical imaging that show promise for differentiation between RIN and recurrent disease in glioma patients. It will take work to realize the full potential of these complimentary imaging forms. 26

27. Acknowledgement Chris Watchman, Russ Hamilton Dino Stea, Marco Marsella Thomas Chong Scott Squire Jamie Holt 27