NEW DISTANT TUMORS IN PATIENTS SUCCESSFULLY TREATED FOR GLIOBLASTOMA MULTIFORMIS:

1. NEW DISTANT TUMORS IN PATIENTS SUCCESSFULLY TREATED FOR GLIOBLASTOMA MULTIFORMIS: 10 YEARS EXPERIENCE G. M. Di Lella; C. Falcone; E. Pravata’; S. Gaudino; A.M. Costantini; C. Colosimo; Dept. of Bio-imaging and Radiological Sciences Policlinico “A. Gemelli”, Catholic University of Rome – ITALY colosimo@rm.unicatt.it

2. New distant tumors in long surviving GBMs.Outline • Background • Patients and Methods • Results • Discussion • Closing Remarks

3. Background - 1 • The term GBM, coined at the beginning of the last century(1), refers to a morphologically highly heterogeneous neoplasm, with microvascular proliferation and/or necrosis (WHO IV)(2) • Two distinct pathologic and genetic pathways(3): • Type I (“Secondary”) - From grade II or III gliomas (p53 mutations) • Type II (“Primary”) - Arising de novo (EGFR amplification) • GBMs also found in the context of multicentric/multifocal gliomas, as defined in 1963(4), with a frequency ranging from 5% - 10% to even 20% (5, 6) • Prognostic factors: Age, KPS-score, extent of resection (7, 8) 1Mallory FB 1914; 2Kleihues et al 2002; 5 Massey et al 1990; 6 Wick et al, 2008; 3Hogaki et al 2007; 4Batzdorf et al, 1963; 7Curran et al, 1993; 8Mirimanoff et al, 2006

4. Background - 2 • Treatment Modalities: • Surgery – Total resection is associated with longer survival (1,2) • RT – Evidence-based efficacy on survival prolongation (3,4) • (CT) - Temozolomide (2000s) + RT is becoming the standard adjuvant treatment in GBMs(5, 6) • 1-y Survival < 30% (7,8) • …Possibleunderlyingmechanisms? • Spread alongunknownanatomicpathways? • New-onsetneoplasms? Most GBMs relapse locally, but 5 – 20% new lesions are reported to emerge remotely from the primary tumour field (9, 10) Not all Distant Relapses explained by either WM continuity infiltration, or by CSF seeding . . . 1Chang et al, 1983; 2 Simpson et al, 1993 3Kristiansen et al, 1981; 4Walker et al, 1978 5Brandes et al, 2008; 6Stupp et al, 2005 7 Capocaccia et al, 2003 8SEER*Stat Release 6.3.5. 2007 9 Wick et al, 2008; 10 Massey et al 1990

5. - Purposes - • To reassess GBMs recurrence modalities in “long-surviving” Patients, with special reference to Distant Recurrences • To describe the MRI features of the new distant relapsing tumors • To hypothesize mechanisms of development for the “new” GBMs

6. Study design & Inclusion Criteria Retrospective evaluation GBM- Pts* surviving > 20 mos Distant Recurrence (DR) without: - relapse in the primary tumor site/surgical field - T2 signal abnormalities between primary and DR - leptomeningeal spreading/involvement * Pts with multicentric/multifocal gliomas at 1°DX were excluded

7. - Patients and Methods - Study Population: • Out of the 750 GBMs in the last 10 years, 68 Pts (9%) survived > 20 mos • In 12/68 Pts (17%)(7M, 5F, 37-58 yrs) newdistant lesions, without recurrence in the primary site, nor leptomeningeal diffusion • All 12 Patients had aggressive resection, RT and CT Imaging Procedures*: • Pre-op CE-MRI scan • Early Post-op CT / CE-MRI scan • Post-op MRI scan (15-45 days after resection), before RT • MRI scan after 30-45 days since RT(/CT) completion • MRI scan every 3-mos for 2-yrs, and later every 6-mos • (since 2005, PWI and MRS were introduced) * All MRI scans performed on 1.5T-system (Signa, GE Medical Systems; Achieva, Philips Medical Systems)

8. Results - 1

9. Results - 2

10. Results • 12/68 longsurvivors had DR, without concomitant local recurrence nor CSF seeding • Mean interval 1° DX/DR = 23.4 mos • All 12 had surgical/autoptical pathological diagnoses of GBM; 12/12 Pts died of progressive DR; • 7/12 new tumors in the contralateral hemisphere; 4/12 in the ipsilateral cerebral hemisphere; 1/12 in the brainstem • CE-DR in 10/12 at appearance • PWI (performed in 4/12): increased r-CBV within the new lesions • MRS (performed in 5/12): increased Cho and Cho/Naa ratio

11. Patient 4Pre-Op – Jan 2004

12. Patient 4– Oct 2005

13. Patient 4 – Jan 2006

14. Patient 5 Pre-op. – Apr 2007 – Jan 2008

15. Patient 5 – Jul 2008 – Dec 2008

16. Patient 5 – March 2009 L9 rCBV: 4.4 L10 rCBV: 2.5 L11 rCBV: 2.8

17. - Discussion 1 -Facts and Hypotheses • Significant number of long-time survivors (12/68, about 17%), developped DR of GBMs , not explainable either by WM continuity infiltration or by CSF seeding . . . • Hypotheses include: • Promoting effects from RT?(1) • Spreading along WM Fibers?(2) • Vascular / Perivascular? • Multicentric / Metachronous GBM? …WhichMechanism? 1Jeremy et al, 2002 2Krishnan et al, 2008

18. Discussion - 2Most recent Hypotheses/Approaches Patient 4 Patient 5 (Lim et al, 2007) • Group I GBMs were Often Multifocal at 1st DX, and had Distant Recurrences • Group IV GBMs were only Solitary Lesions, and recurred contiguously with the resection cavity (Krishnan et al, 2008)

19. - Closing Remarks - • The development of “new” distant GBMs after successful treatment of the primary tumor is a relatively frequent occurrence in long-time survivors . . . • . . . Thus , during MRI f-u of GBM Ptsa Careful Scrutiny Must be Devoted to the Entire Brain • More effective treatments and longer survival time may allow development of “new” GBMs, that could be considered Multicentric Metachronous Malignant Gliomas • Such an hypothesis would revalue the old theory of the GBM as a “cancer of the brain as whole”, that would be easier to accept on the basis of our current knowledge in oncogenesis