1. S. CONDETTE-AULIAC 1, A. BOULIN 1, O. COSKUN 1, L. BOZEC-LE MOAL 2, S. ALDEA 3, S.GUIEU 1, G. RODESCH 1. 1 Neuroradiology department, 2 Oncology department, 3 Neurosurgery department FOCH hospital Suresnes France HOW TO DIAGNOSE TUMOR PROGRESSION ON MRI ? RECURRENCE OF HIGH-GRADE GLIOMAS TREATED WITH BEVACIZUMAB AND IRINOTECAN : Symposium Neuroradiologicum 2010

2. Surgical resection Radiotherapy Concomitant and adjuvant chemotherapy (temozolomide) When Recurrence : New surgery if possible Second line chemotherapy with the association of BEVACIZUMAB (anti VEGF) and IRINOTECAN TREATMENT OF GLIOBLASTOMAS IN ADULTS

3. Mac Donald criteria : based on post gadolinium sequences Complete response (CR) : disappearance of any contrast enhancement Partial response (PR): 50% decrease in the largest cross- sectional area of enhancement Minimal partial response(mPR): decrease of 25-49% in the largest cross-sectional area of enhancement (Norden et al Neurology 2008;70:779-787) EVALUATION OF THE RESPONSE TO TREATMENTS

4. Complete response Hydrocephalus Tumor infiltration Before treatment First evaluation (4 weeks)

5. To report the MRI expression of the effects of antiangiogenic drugs in patients treated for recurrence of high grade gliomas To precise the signs of evolutivity of those tumors on MRI To discuss the ability of the different MRI sequences to diagnose the evolutivity. AIM OF OUR STUDY

6. Retrospective study : since 2008, 18 patients Recurrent high grade gliomas Second line of chemotherapy associating bevacizumab and irinotecan 45 MRI were performed on GE LightSpeed 1.5T MRI with the same sequences T1WI, T2WI, DWI, PWI, FLAIR, T1WI G+ and infusion of gadoteric acid 0.5cc/kg (5 to 7 cc/s) MRIs have been performed few weeks after the beginning of treatment (2 to 8 weeks, mean 5 weeks) and every 2 months Comparison to pre-treatment MRI MATERIAL AND METHODS

7. Eliminating poorly perfused erratic tumor vasculature, perfusion is relatively normalized :  rCBV Extravasation of contrast in interstitial spaces decreases :  enhancement The initial decrease of enhancement is the result of “vascular pruning” and thus not a true indicator of tumor activity, suggesting an even higher infiltrative tumor behavior : Flair hypersignal Cooption via pre-existent vasculature that lead to distant lesion ANTIANGIOGENIC EFFECTS Bao et al cancer res 2006;66:7843-784 Essig et al Eur Radiol 2001;11:2004-2010

8. Perfusion criterias : r CBV Enhancement criterias : volume of the lesion Intensity of the enhancement New enhancement T2/FLAIR criterias Volume of hypersignal (oedema / lesion) Intensity of hypersignal New hypersignal 2cm beyond the lesion EVALUATION CRITERIAS

9. What have we observed ? 3 patients with no response and progression of the lesion and clinical failure 2 patients with disappearance of the enhancement with decreased size of the lesion and no other abnormality : complete response ? 9 patients with partial or min partial response on all sequences 4 patients had discordant imaging SENSITIVITY TO TREATMENT?

10. Decrease in oedema in all patients SENSITIVITY TO TREATMENT?

11. 11 patients with response: Decrease in intensity of contrast enhancement up to disappearance Decrease in lesion size (gado+) Decrease in the rCBV Decrease in intensity of hypersignal FLAIR SENSITIVITY TO TREATMENT

12. 4 patients with discordant imaging Local response but infiltrative lesion on FLAIR : 2 SENSITIVITY TO TREATMENT

13. 4 patients with discordant imaging Decrease in enhancement size, hypersignal FLAIR but no decrease in rCBV SENSITIVITY TO TREATMENT

14. 4 patients with discordant imaging Reduction of the lesion in all sequences but slight increase of a second lesion (FLAIR) and new neovascularization spot SENSITIVITY TO TREATMENT

15. When all sequences are concordant, we can assess the sensibility to treatment A mismatch between the sequences, especially new hypersignal FLAIR or new spot of neoangiogenesis allows the diagnosis of the tumor progression The anti oedemateous effect of the treatment was observed in all patients PRELIMINARY FINDINGS

16. Local recurrence : within a 2 cm margin around the index lesion Diffuse recurrence : lack of concordance between areas of increased enhancement and areas of hyperintensity seen on FLAIR beyond this margin of 2 cm * Distant lesion : foci hypersignal on FLAIR even without enhancement (may occur via cooption of pre-existent vasculature) Our series : Local recurrence : 9 Distant lesion (>2 cm) : 2 Diffuse progression : 4 RECURRENCE PATTERNS *Norden et al Neurology 2008;70:779-787 **Essig m Eur Radiol 11:2004-2010

17. DISTANT LESION DIFFUSE PROGRESSION

18. 9 patients 5 FLAIR more sensitive than enhancement (3 of them no enhancement) 2 rCBV increased until the enhancement appears LOCAL PROGRESSION

19. Oct 2008

20. Flair and perfusion sequences seem to be the first sequences showing lesion progression Contrast enhancement always associated to FLAIR abnormalities but FLAIR abnormalities without contrast enhancement One case of ↑ rCBV before FLAIR hypersignal appearance DWI didn’t show decreased adc before FLAIR hypersignal appearance TO PROPERLY DIAGNOSE EVOLUTIVITY Response Assessment in Neuro-Oncology (RANO) working group Wen P. et al J Clin Oncol 2010;28:1963-1972

21. Patterns of progress are different from other treatments Contrast enhancement not directly related to the increase or decrease in tumor Accurate assessment of tumor progression requires the use of FLAIR and perfusion sequences. Multimodality MRI New sequences? SPECTRO MR CONCLUSION

22. BOULIN A. MD COSKUN O. MD GUIEU S. MD RODESCH G. MD PHD BOZEC-LE MOAL L. MD Neurooncology Dpt ALDEA S. MD, BENNIS S. MD, MIREAU E. MD, GAILLARD S. MD Neurosurgery Dpt MOISSON P. MD Radiotherapy Dpt BERNIER M. MD Anatomo-pathology Dpt EVRARD S. MD, WANG A. MD, BOURDAIN F. MD, DECROIX JP. MD, GRAVELEAU P. MD Neurology Dpt ACKNOWLEDGMENTS