Concepts for a personalized neurosurgical oncology. XXIV Annual Conference Pietro Paoletti 27. November 2015

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1 Concepts for a personalized neurosurgical oncology Jörg-Christian Tonn Dept. of Neurosurgery Ludwig-Maximilian University München Großhadern Germany XXIV Annual Conference Pietro Paoletti 27. November 2015

2 Disclosures Consultant MerckSerono, Roche, medac, Celldex BrainLab, Siemens Grants Deutsche Forschungsgemmeinschaft (DFG) German Cancer Research Foundation (Deutsche Krebshilfe)

3 You can only offer personalized glioma surgery if you obtain a maximum of patient-specific information Microsurgical Resection Stereotactic Biopsy

4 Which glioma? The upcoming WHO classification Molecular marker Diffuse Glioma IDH mut with 1p/19q codel Diffuse Glioma IDH mut no 1p/19q codel Diffuse Glioma no IDH mut + 1p/19q codel IDH 1/2 mutant mutant wildtype 1p/19q codeleted intact intact Histology olidendroglial astrocytic astrocytic WHO grade II or III II or III (rarely IV) IV (rarely II or III) Median OS > 15 years 8-12 years < 2-3 years Weller, Reifenberger, Tonn, Wick, in press 2015

5 Which glioma? The upcoming WHO classification Molecular marker Diffuse Glioma IDH mut with 1p/19q codel Diffuse Glioma IDH mut no 1p/19q codel Diffuse Glioma no IDH mut + 1p/19q codel IDH 1/2 mutant mutant wildtype 1p/19q codeleted intact intact Histology olidendroglial astrocytic astrocytic WHO grade II or III II or III (rarely IV) IV (rarely II or III) Median OS > 15 years 8-12 years < 2-3 years Weller, Reifenberger, Tonn, Wick, in press 2015

6 Which glioma? The upcoming WHO classification Molecular marker Diffuse Glioma IDH mut with 1p/19q codel Diffuse Glioma IDH mut no 1p/19q codel Diffuse Glioma no IDH mut + 1p/19q codel IDH 1/2 mutant mutant wildtype 1p/19q codeleted intact intact Histology olidendroglial astrocytic astrocytic WHO grade II or III II or III (rarely IV) IV (rarely II or III) Median OS > 15 years 8-12 years < 2-3 years Weller, Reifenberger, Tonn, Wick, in press 2015

7 Which glioma? The upcoming WHO classification Molecular marker Diffuse Glioma IDH mut with 1p/19q codel Diffuse Glioma IDH mut no 1p/19q codel Diffuse Glioma no IDH mut + 1p/19q codel IDH 1/2 mutant mutant wildtype 1p/19q codeleted intact intact Histology olidendroglial astrocytic astrocytic WHO grade II or III II or III (rarely IV) IV (rarely II or III) Median OS > 15 years 8-12 years < 2-3 years Weller, Reifenberger, Tonn, Wick, in press 2015

8 Which glioma? The upcoming WHO classification Molecular marker Diffuse Glioma IDH mut with 1p/19q codel Diffuse Glioma IDH mut no 1p/19q codel Diffuse Glioma no IDH mut + 1p/19q codel IDH 1/2 mutant mutant wildtype 1p/19q codeleted intact intact Histology olidendroglial astrocytic astrocytic WHO grade II or III II or III (rarely IV) IV (rarely II or III) Median OS > 15 years 8-12 years < 2-3 years No decision about therapy without molecular marker! Weller, Reifenberger, Tonn, Wick, in press 2015

9 Where is it / extent and borders? Size and localize Is it all the same? Heterogeneity Molecular marker

10 WYSIWYG? T1/T2 +/- CE Perfusion-MRI DSC - CBV DWI PET

11 Outcome prediction in patients with glioblastoma by using imaging, clinical, and genomic biomarkers: focus on the nonenhancing component of the tumor. Jain R et al, Radiology Aug;272(2): rcbv of the non enhancing tumor as the top predictor; also important were KPS, age at diagnosis, and NER crossing the midline not CE-MRI Prospective glioma grading using single-dose dynamic contrast-enhanced perfusion MRI. Jain KK et al, Clin Radiol Jul 4

12 18 FET PET High Grade Gliomas T 2 18 FET-PET T 1 (Gd) Fusion Fusion Tumorvolume: T 2 > 18 FET-PET > T 1 -GD La Fougère et al., NeuroOncology 2011

13 Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning. Arbizu J, Tejada S, Marti-Climent JM, Diez-Valle R, Prieto E, Quincoces G, Vigil C, Idoate MA, Zubieta JL, Peñuelas I, Richter JA. Eur J Nucl Med Mol Imaging. 2012;39:771-81

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15 Prognostic value of 18 FET-PET BTV for the clinical course in newly diagnosed glioblastoma Suchorska et al, Neurology, 2015 A 70% of GB were larger in 18 FET-PET than in CE-MRI BTV B R R R L L L R L Multivariate Analysis OS Factor MGMT methylation p < KPS p < TAC p < BTV ( 18 FET-PET) p < 0.001

16 Where is it / extent and borders? Size and localize extent and resection / extent of resection Is it all the same?

17 Volume 14 ml 113 ml (87,5% no CE)

18 Volume 14 ml 113 ml (87,5% no CE)

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20 Microsurgery Improved results due to fluorescence guided resection (Stummer et al., Lancet Oncol 2006) /139 p < white light 25 47/131 ALA WL Parameter overall survival multivariate p value ALA UV-light Residual tumor no / yes p < KPS 80 / > no residual tumor residual tumor Age 55 / > Eloquent areas no / yes

21 overall survival (Stummer et al., Lancet Oncol 2006) Fluorescence Guided Resection (5-ALA): Overall survival stratified by residual tumor volume p=0.34 Time [months] 0 ccm > ccm > 1.5 ccm p=

22 OS 16, 13.8, 12.8, 12.5 months

23 Whereas the 78% threshold represents the minimum value at which a survival benefit is seen, RPA selected 95% as the most significant predictor of survival in patients with GBM, emphasizing the added value of a complete resection Neverthless, the usual limitations of a retrospective analysis still apply, particularly with respect to the risk of selection bias.

24 Ann Oncol Dec;24(12):

25 Complete resection of contrast enhancing tumor volume is associated with improved survival in recurrent GB Arm A Arm B DIRECTOR trial Weller M et al: Clin Cancer Res. 2015; 21(9): MGMT+/- MGMT+/- Comparison of two different TMZ re-challenge regimens: Arm A: 1 week on/1 week off vs. Arm B: 3 weeks on/1 week off 25

26 Complete resection of contrast enhancing tumour volume is associated with improved survival in recurrent GB Does surgery pe se matter or only complete resection? current analysis based on the DIRECTOR trial, a prospective randomized multicenter trial comparing two dose-intensified temozolomide (TMZ) regimens at recurrence of glioblastoma GBM Primary therapy Recurrence Analysis EOR for PFS/OS Surgery/No surgery TMZ 1week on/1week off TMZ 3 weeks on/1week off 26 Suchorska et al, ASCO 2015 KLINIKUM DER UNIVERSITÄT MÜNCHEN NEUROSURGICAL DEPARTMENT

27 Complete resection of contrast enhancing tumor volume is associated with improved survival in recurrent GB 27 Results: Surgery for recurrence Yes 71 No 34 p Age at diagnosis Median (years) Range (years) Gender: N (%) Male 48 (67.6) 21 (61.8) Female 23 (32.4) 13 (38.2) MGMT promoter: N (%) Methylated 31 (43.7) 15 (44.1) Unmethylated 40 (56.3) 19 (55.9) First-line therapy: Number of maintenance TMZ cycles Median Range Time to first progression (months) Median Range Tumor volume at recurrence (cm 3 ) Median Range Tumor volume at study entry (cm 3 ) Median <0.001 Range KPS at study entry: N (%) (56.3) 20 (58.8) (31.0) 9 (26.5) <70 9 (12.7) 5 (14.7) Steroids at study entry: N (%) Yes KLINIKUM 20 (31.3) DER UNIVERSITÄT 8 (28.6) MÜNCHEN NEUROSURGICAL DEPARTMENT No 44 (68.7) 20 (71.4)

28 Complete resection of contrast enhancing tumour volume is associated with improved survival in recurrent GB Results: Re-operation: yes/no yes (n=71) no (n=34) yes (n=71) no (n=34) p = 0.63 p = 0.36 p = 0.63 Progression Free Survival2 (months) Post Recurrence Survival (months) 28 Suchorska et al, ASCO 2015 KLINIKUM DER UNIVERSITÄT MÜNCHEN NEUROSURGICAL DEPARTMENT

29 Complete resection of contrast enhancing tumour volume is associated with improved survival in recurrent GB Results: Extent of resection GTR (n=40) incomplete (n=19) GTR (n=40) incomplete (n=19) p = 0.02 p <0.001 Progression Free Survival2 (months) Post Recurrence Survival (months) Suchorska et al, ASCO 2015 KLINIKUM DER UNIVERSITÄT MÜNCHEN NEUROSURGICAL DEPARTMENT

30 Complete resection of contrast enhancing tumour volume is associated with improved survival in recurrent GB Results: Extent of resection GTR (n=40) incomplete (n=19) no surgery (n=34) GTR (n=40) incomplete (n=19) no surgery (n=34) p = p = Progression Free Survival2 (months) Post Recurrence Survival (months) 30 Suchorska et al, ASCO 2015 KLINIKUM DER UNIVERSITÄT MÜNCHEN NEUROSURGICAL DEPARTMENT

31 Complete resection of contrast enhancing tumour volume is associated with improved survival in recurrent GB Results: Multivariate analysis Hazard ratio and p 95% CI Extent of resection: GTR versus incomplete 0.42 ( ) Age at study entry: versus 55+ years 1.25 ( ) MGMT promoter: methylated versus unmethylated 0.58 ( ) KPS at study entry: % versus KPS 50-80% 0.82 ( ) Steroids at study entry: no versus yes 0.82 ( ) Results: QoL analysis Patients receiving surgery had higher cognitive functioning values after 8 weeks (p=0.046) 31 Patients who received an incomplete resection were more likely to suffer from general motor dysfunction (p=0.04) and to have a worse global health status (p=0.008) compared to those who received GTR Suchorska et al, ASCO 2015 KLINIKUM DER UNIVERSITÄT MÜNCHEN NEUROSURGICAL DEPARTMENT

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33 Intraoperative Neuronavigation Multiparametric Imaging

34 Intraoperative Neuronavigation Intraoperative Imaging update via ius

35 Gold-Standard for preservation of function?

36 Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. De Witt Hamer PC et al, J Clin Oncol Jul 10;30(20): Permanent severe neurological deficit: 3.4% with mapping 8.2% without mapping gross total resection (as by post-op MRI): 75% with mapping 58% without mapping

37 Where is it / extent and borders? Size and localize Is it all the same? Heterogeneity Molecular marker

38 MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma Gill BJ et al, Proc Natl Acad Sci U S A. 2014;111(34): samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM - samples from the NE regions predominantly resembled the neural subtype

39 3,0 2,0 1,0 0, ,0 6,0 5,0 4,0 PFS (2 yrs): 78%, 35%, 26% fraction hotspot 2% - 90% Size of hotspot: no prognostic relevance 3, ,0 2,0 1,0 0, ,0 45 % of suspected LGG were anaplastic WHO III or GBM! 6,0 5,0 4,0 Kunz et al, NeuroOncol. 2011; 13:307 3, homogeneous increasing TAC heterogeneous TAC homogeneous decreasing TAC p=0.002 Thon N et al, Int J Cancer 2015 n=98 censored

40 PET- guided microsurgical resection

41 PET- guided microsurgical resection Focus adjusted resection

42 Preoperative MRI/FET-PET (36y/o female w suspected LGG WHO II)

43 Postoperative MRI/FET-PET after focus-adjusted resection ( WHO III)

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46 Homogeneous distribution of biomarker (Tp53, MGMT, LOH1p/19q, IDH1) solid tumor Risk of false negative results infiltrative zone Success rate of molecular-genetic analyses: > 98% Morbidity rate: < 1% (> 900 biopsy procedures ) Thon et al: J Neuropathol Exp Neurol, 09

47 Where is it / extent and borders? Size and localize Is it all the same? Heterogeneity Molecular marker

48 unmethylated MGMT promotor MGMT promotor region MGMT gene active Transcription/Translation TMZresistent MGMT promotor methylation CH CH CH CH CH 3 3 MGMT promotor region MGMT gene inactive Transcription/Translation TMZsensitive

49 unmethylated MGMT promotor MGMT promotor region MGMT gene active Transcription/Translation TMZresistent MGMT promotor methylation CH CH CH CH CH 3 3 MGMT promotor region MGMT gene inactive Transcription/Translation TMZsensitive Hegi et al 2008

50 Thon et al 2010 Hegi et al 2008

51 Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised phase 3 trial. Wick W et al, Lancet Oncol :707 MGMT pos + TMZ MGMT neg + TMZ OS 373 pts, age > 65 ys, KPS > 60

52 Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG Cairncross G et al, J Clin Oncol :337 Epub 2012 LOH 1p/19q PCV+RT vs RT only 14.7 vs 7.3 yrs; p = 0.03 no codeletion PCV+RT vs RT only 2.6 vs 2.7 yrs; p = 0.39

53 WHO-Grad-II/III/IV-Glioma IDH-1/2 wildtype mutant Histology WHO-Grade IV WHO-Grade II/III WHO-Grade II/III/(IV) Age > 65 MGMT - RT MGMT + TMZ or TMZ/RT TMZ Age 65 MGMT - MGMT + RT TMZ/RT TMZ 1p/19q intact TMZ or PCV or RT 1p/19q codeletet RT/PCV (TMZ/RT TMZ) Weller, Reifenberger, Tonn, Wick, in press 2015 Biomarker Therapy

54 Personalized tumor therapy