1. NEW DISTANT TUMORS IN PATIENTS SUCCESSFULLY TREATED FOR GLIOBLASTOMA MULTIFORMIS: 10 YEARS EXPERIENCE Dept. of Bio-imaging and Radiological Sciences Policlinico “A. Gemelli”, Catholic University of Rome – ITALY G. M. Di Lella; C. Falcone; E. Pravata’; S. Gaudino; A.M. Costantini; C. Colosimo ; 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) 1 Mallory FB 1914; 2 Kleihues et al 2002; 3 Hogaki et al 2007; 4 Batzdorf et al, 1963; 5 Massey et al 1990; 6 Wick et al, 2008; 7 Curran et al, 1993; 8 Mirimanoff 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) 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... 1 Chang et al, 1983; 2 Simpson et al, 1993 3 Kristiansen et al, 1981; 4 Walker et al, 1978 5 Brandes et al, 2008; 6 Stupp et al, 2005  1-y Survival < 30% (7,8) …Possible underlying mechanisms? Spread along unknown anatomic pathways? New-onset neoplasms? 7 Capocaccia et al, 2003 8 SEER*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 - 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) new distant lesions, without recurrence in the primary site, nor leptomeningeal diffusion All 12 Patients had aggressive resection, RT and CT 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) Imaging Procedures*: Study Population: * All MRI scans performed on 1.5T-system (Signa, GE Medical Systems; Achieva, Philips Medical Systems)

8. Results - 1 Pt.Primary Site Distant Recurrence Site Time To Relapse (months) Survival after Recurrence (months) Overall Survival Path. DR Evidence 1 L ParietalBrainstem38846Autopsy 2 R FrontalL Frontal215262 nd surg 3 L TemporalR Frontal223252 nd surg 4 L FrontalR Temporal246302 nd surg 5 L Parieto-OccR Frontal2313362 nd, 3 rd surg 6 L TemporalR Temporal2412362 nd surg 7 R TemporalL Frontal18725 Autopsy 8 L TemporalR Temporal174212 nd surg 9 L FrontalL Temporal315362 nd surg 10 L OccipitalL Frontal20323 Autopsy 11 L TemporalL Parietal2512372 nd surg 12 R TemporalR Parietal21627Autopsy Mean:23.47.130.5

9. Results - 2 Pt. DR Size (mm) CE (Y/N, Pattern) PWI (r - CBV) MRS (SV) 115NO N/A 218Yes, SOLID↑ (2.9)↑ Cho – Cho/Naa 325Yes, RING↑ (3.2)↑ Cho – Cho/Naa 424Yes, SOLID N/A 527Yes, FAINT↑ (2.0)↑ Cho – Cho/Naa 633Yes, RING N/A ↑ Cho – Cho/Naa 724NO↑ (3.0) N/A 836Yes, RING N/A 927Yes, SOLID N/A 1028Yes, SOLID N/A ↑ Cho – Cho/Naa 1121Yes, RING N/A 1231Yes, RING N/A

10. Results 12/68 long survivors 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 4 Pre-Op – Jan 2004

12. Patient 4 – Oct 2005

13. Patient 4 – Jan 2006

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

15. Patient 5 – Jul 2008 – Dec 2008

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

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? 1 Jeremy et al, 2002 2 Krishnan et al, 2008 …Which Mechanism?

18. Discussion - 2 Most recent Hypotheses/Approaches (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) Patient 4 Patient 5

19.  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 Pts a 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 - Closing Remarks -