Glioma. Glioma : Outline Kazi Manir. MD,DNB,ECMO R.G.Kar Medical College,Kolkata

Transcription

1 Glioma Glioma : Outline Kazi Manir MD,DNB,ECMO R.G.Kar Medical College,Kolkata

2

3 Non-neuronal cells having capacities to divide. Astrocytes control chemical environments of neurons & blood flow (fmri detection) Oligo-dendrocytes produces myelin sheath in CNS. Glial cells

4 Devita,Cancer 10 th edition page 1404

5

6 WHO classification 2016 Summery of Major changes: Restructuring of diffuse gliomas, incorporating genetically defined entities IDH-wild type and IDH-mutant GBMs

7 Grading

8 Molecular outline

9

10

11

12 Devita 10 th edition Page 1406

13

14 1p/19q deletion Brandner et al 2015

15 Prognostic and predictive Oligo-dendroglial > Oligo-astrocytic histology Response to PCV and TMZ strongly correlates with co-del. Longer PFS and better response to Chemotherapy

16 Diagnostic role: Astrocytoma vs Oligo-astrocytoma Oligo-dendroglioma

17 ESMO Master class 2016 Zurich

18 Isocitrate Dehydrogenase (IDH): IDH 1 R132H Mutation (MC) and codon 172 mutation in mitochondrial IDH2 gene (rare) Grade II & Grade III astrocytic Grade II % Grade III Oligodendroglial Secondary GBM (from astrocytoma) Favorable prognosis in Grade III>II Low grade prognostic significance doubtfull High diagnostic value: IDH IHC +ve in low grade/anaplasitc oligodendroglioma -ve in primary GBM clear cell ependymoma Pilocytic astrocytoma GBM with oligo-dendroglial differentiation

19 ESMO Master class 2016 Zurich

20 MGMT Promoter methylation O6-Methylguanin-methyltransferase (MGMT, AGAT), a DNA repair protein, counteracts the effect of alkylating agents. MGMT Promoter methylation makes MGMT inactive. Prognostic and predictive in Malignant Glioma. Methylation specific PCR based detection.

21 MGMT Promoter methylation Brander et al 2015 ESMO Master Class Zurich 2016

22 ESMO Master class 2016 Zurich

23 ATRX loss (Alfa Thalassemia/Mentally Retarded X linked 52 /RAD 52) Can be detected by IHC/Gene Sequencing Found in exclusively in IDH mutant astrocytoma 67% Grade II and 73% in Grade III astrocytoma Rarely seen in GBM Diagnostic: to differentiate from Oligo astro/dendro Mutually exclusive with 1p/19q co-deletion Survival benefit adding TMZ/PCV in ATRX mutant AA Wistler B. et al. Acta Neuropathol 2013

24 Telomerase Reverse Trascriptase (TERT) mutation 75% in GBM and 18% in Grade II & III TERT promoter mutation presents with 1p/19q codeletion Mutually exclusive with IDH1 in GBM/astro Rarely presents with IDH1 in Oligodendroglioma Prognostic role still unclear Survival of GBM: IDH mutation only (42m) > IDH + TERT both wild type (16m) > TERT mutation only (11m) Nonoguchi N et al Acta Neuropathol 2013

25 B RAF V600E mutation In Refractory /recurrent BRAF mutant Pediatric Low grade Glioma Debrefeninb improves outcome with manageable side effects Kieren et al ESMO congress Copenhagen 2016

26 Other Mutations Histone H3F3A mutation: Paediatric Brainstem Glioma>adult GBM Coexists with ATRX mutation EGFR amplification: 28% primary IDH wild type GBM CIC mutation (19q) & FUBP1 mutation (1p): Additional diagnostic tool (IHC) to classify oligo vs astro tumors ahead of 1p 19 q test

27 Integrated diagnostic approach S. Brandner and A. von Deimling 2015

28 Integrated Diagnostic approach Diagnostic Panel: Non GBM Diagnostic Panel : GBM

29 Franceschi E. ESMO Congress September 2016

30 Radiological evaluation CT MRI DWI ADC MRI MR Perfusion: Dynamic Susceptibility Contrast Imaging (DSCI) relative cerebral blood flow volume (rcbv) relative cerebral blood flow volume (rcbf) Arterial Spin Labeling Perfusion Imaging (ASL MRI) MR Spectroscopy PET

31 Radiological evaluation MRI gold standard Most useful T1-weighted sagittal images Gd enhanced and unenhanced T1 axial images T2-weighted axial images CEMR helps :benign/malignant & low/high grade Commonly : Low grade Glioma do not enhance (except PCA and PXA) Presence of calcification is unique for Oligodendroglioma Negative prognostic factors include: the degree of necrosis the degree of enhancement deep location (e.g. thalamus)

32 CT: GBM irregular thick margins: iso to slightly hyper attenuating (high cellularity) irregular hypodense centre representing necrosis marked mass effect surrounding vasogenic oedema hemorrhage occasionally seen calcification is uncommon intense irregular, heterogeneous enhancement of the margins is almost always present

33 MRI: GBM T1 hypo to isointense mass within white matter central heterogeneous signal (necrosis, intratumoural haemorrhage) T1 C+ (Gd) enhancement is variable but is almost always present typically peripheral and irregular with nodular components usually surrounds necrosis T2/FLAIR hyperintense surrounded by vasogenic oedema flow voids occasionally seen

34 GBM : T1 and T1 contrast

35 GBM : T1 and T1 contrast

36 GBM: T2 and FLAIR

37 Diffusion weighted MRI Apparent Diffusion Coefficient (ADC) solid component elevated signal on DWI is common in solid/enhancing component ADC values correlate with grade WHO IV (GBM) = 745 ± 135 x 10-6 mm 2 /s WHO III (anaplastic) = 1067 ± 276 x 10-6 mm 2 /s WHO II (low grade) = 1273 ± 293 x 10-6 mm 2 /s

38 MR spectroscopy Typical spectroscopic characteristics include choline: increased lactate: increased lipids: increased NAA: decreased myoinositol: decreased

39 MRS Lesion site

40 MRS Normal Brain site

41 MR perfusion DSCI ASL MRI Helps to differentiate : Glioma/TB Low grade/high grade Radiation Necrosis/Recurrence rcbv (also? rcbf) elevated compared to lower grade tumours and normal brain Thomsen H et al. Acta Radiologica 2012

42 GBM T1 Axial T1 C+ Axial

43 GBM T2 Axial T2 FLAIR

44 GBM ADC DWI

45 GBM DSCI : CBV CBV

46 D/D with GBM cerebral metastasis may look identical both may appear multifocal metastases usually are centred on grey-white matter junction and spare the overlying cortex rcbv in the 'oedema' will be reduced primary CNS lymphoma should be considered especially in patients with AIDS, as in this setting central necrosis is more common otherwise usually homogeneously enhancing

47 Low grade Glioma T1 and T1 contrast

48 Low Grade Glioma: T2 and FLAIR

49

50 Glioma: Diffuse Brainstem Glioma Site: Mesencephalic Pontine (70%) (Diffuse Intrinsic Pontine Glioma): DIPG Medullary May present with obstructive hydrocephalus CT: Typically hypodense with little enhancement. MRI: T1: decreased intensity T2: heterogeneously increased T1 C+ (Gd): usually minimal (can enhance post RT) DWI: usually normal, occasionally mildly restricted

51 DIPG T2 T1 + C

52 Focal Brain stem Glioma Children /NF1 associated Tectal Plate more common May be associated with Hydrocephalus CT: Homogenous expansion of tectal plate No enhancement MRI: T1: iso to slightly hypointense to grey matter T2: hyperintense to grey matter T1 C+ (Gd): usually no enhancement

53 Axial T2 FLAIR T1 + C

54 Opto chiastmatic Glioma Children/NF1 association H/P: JPA Most common Indolent course Heterogenous with mixed solid & Cystic components MRI: T1: almost always hypointense T2: hyperintense FLAIR: hyperintense T1 C+ (Gd): solid components of large tumours often contrast enhance T1 +C Fat Saturation

55

56

57

58

59 Post surgical Treatment Personalised appraoch

60 Post surgical Treatment outline

61 ESMO Master class Zurich 2016

62

63 ASTRO guideline 2016 Benefit of Adj RT after Biopsy/Sx Benefit of CCT/Adj TMZ

64 ASTRO guideline 2016 Dose & # in patients <70 years with good PS

65 Elderly patients (>70) ASTRO guideline 2016

66 ASTRO guideline 2016 Poor PS: Re RT in recurrence:

67 Target Volume: ASTRO guideline 2016

68 Whole Brain RT 2phase Partial Brain RT (3D RT) Focal RT 3DCRT IMRT VMAT

69 GBM contouring guideline 2016 Preparatory phase: Immobilization mask: head neutral 1-3mm CT : Flat couch: vertex to C3 Up to date ( 2weeks) CEMRI to be fused If MRI contraindicated Use CECT T1 + T2/FLAIR sequence dwmri, MRS, 18F-FET PET or [11C]methionine PET : investigational

70 General facts T2/FLAIR signals fluctuate depending on tumor mass-effect and postop edema. Contouring only based on T2/FLAIR sequence overestimates CTV volume. GBM is not a focal but infiltrative disease. Tumor cell may found varying density in whole Brain. Recurrence may occur due to sub-therapeutic doses (OAR limiting doses) 80% recurrences occur <2cm area of contrast enhanced lesions on CT or MRI.

71 MRI scan : Principle Post op MRI fused with planning CT: MUST Post op MRI (<48 hrs of Sx) : underestimates (shifting of brain/potential rec) Ideal timing: 2weeks of simulation Contrast enhanced T1 + T2/FLAIR Thin slice 3mm 1mm isotropic MPRAGE image: better white vs grey matter difference. Investigational: PWI/DWI MRI.

72 GTV: Resection cavity (if present) + all T1 CE areas with out T2/FLAIR peri-tumoral edema. Caveats: Post op gliosis mimics CE residual tumor. Secondary GBM (background of Non CE glioma) needs inclusion of T2 hyper intensity with T1 CE areas.

73 CTV: GTV + 2cm margin all around along white matter tracts Edit: Skull (0 mm, using bone window) Ventricles (5 mm) Falx (5 mm) Tentorium cerebelli (5 mm) visual pathway/ chiasm & brainstem (each 0 mm)

74 CTV issues FLAIR derived volumes > T2 derived volumes Some schools : don t edit CTV : include all T2 hyper intense areas No outcome difference Edema vs residual tumor is difficult to distinguish

75 Niyazi M et al. Radiother Oncol 118(2016)

76

77

78

79

80

81 OAR Niyazi M et al. Radiother Oncol 118(2016)

82 PTV margin : Uncertainties of CT MRI fusion & set up. Ideally departmental fixation protocol and QA protocol specific. Modern Linac with on/offline correction 3-5mm PTV margin suffice.

83 Technique Small spherical frontal/parietal tumor: 3DCRT IMRT/VMAT: Temporal /Insular Close proximity to orbit or brainstem Irregular shape VMAT similar conformity with 3DCRT with faster planning and delivery time Dose prescription: (ICRU 50 & 62) 100% at the isocentre, ensuring that the 95% isodose surface covers at least 95% of the PTV.

84 Immunotherapy: current approaches ESMO Congress 2016 Copenhagen

85 Major ongoing changes in Immunotherapy Rindopepimut for EGFRvIII-positive GBM? ICT-107 for HLA2-positive glioblastoma? Checkpoint inhibitors

86

87 ReACT trial

88 Immune checkpoint inhibitors Immune checkpoint inhibitors may exert strong anti-tumor activity: Melanoma: anti-ctla-4 alone vs. anti-pd-1 alone vs. combined treatment Pembrolizumab and nivolumab have been approved for advanced melanoma and other tumor entities May these drugs also mount anti-tumor immune responses against neoplasms in the CNS?

89 Current status PD1/PDL1 axis in GBM PD-L1 is expressed in human glioblastoma in vivo. Major prognostic role for PD-L1 expression in glioblastoma not defined. The significance as a biomarker of tumoral versus non-tumoral PD-L1 expression remains to be determined in glioblastoma, like in many other cancers. Preclinical studies demonstrate activity of PD- 1 inhibition in rodent glioma models.

90 CheckMate 143 : Phase II

91

92 CheckMate 143: Phase II to Phase III

93

94 SPECIAL SITUATION

95 Paediatric Glioma Gliomas are the most common primary brain tumors in children Histologically, they can be either low grade or high grade tumors Molecular biology now better defines subgroups of pediatric gliomas Surgery remains the mainstay of treatment for PLGG with exceptions PLGG is associated with good long-term outcomes (20-year OS~90%) Therapeutic regimen needs to take into account long-term effects Chemotherapy preferred as initial therapy in PLGG (after surgery) Pediatric HGG is fortunately much less common than PLGG Pediatric GBM is molecularly very distinct from its adult counterpart Unfortunately it is associated with universally dismal outcomes (as in adults) Targeted therapy likely to be the future in most pediatric gliomas

96 Management of Pediatric Low Grade Glioma Surgical resection: treatment of choice for resectable tumors Maximal safe resection: paradigm of choice during surgery Gross total resection/near total resection: curative treatment Surgical decompression/biopsy: still needed in vast majority Eloquent sites (optic pathway, brainstem, thalamus): difficult to biopsy Achieves immediate symptom relief by decompressing the brain Enables accurate histomorphological diagnosis (tumor type and grade) Provides tumor tissue for appropriate molecular testing Facilitates further adjuvant therapy (as and when necessary)

97 Some important exceptions to surgical resection 1: Focal Tectal Plate Glioma Clinically indolent tumor Presents with hydrocephalus Only CSF diversion (ETV) recommended 2: Optic Pathway Glioma (OPG) in NF1 One of the diagnostic criteria for NF1 Relatively slow growing/indolent course May regress/resolve spontaneously 3: Diffuse Intrinsic Pontine Glioma (DIPG) Diffuse expansion of pons Triad of signs & symptoms Aggressive biological behaviour

98 What after surgery - When to treat Further Adjuvant Therapy vs Observation Severe tumor-related symptoms (deficits, diencephalic syndrome) Unequivocal clinico-radiological evidence of tumor progression Recurrent tumor after achieving gross total resection previously COG Recommendations for Therapy

99 General Approach to Management of PLGG Stucklin et al, Neuropaediatrics 2016

100 BRAF signalling pathway: implicated in significant proportion of PLGG

101 BRAF alterations in PLGG: diagnostic, prognostic, or predictive? Useful aid for confirming diagnosis

102 Targets and opportunities for targeted therapy Penman et al, Front Oncol, 2015

103 Pediatric Glioblastoma

104 Management of Pediatric HGG including GBM Maximal safe resection remains the first-line therapy for pediatric HGG Post-operative adjuvant radiochemotherapy improves outcomes Focal Conformal RT (55.8Gy-59.4Gy in fx) is the current standard Concurrent and adjuvant temozolomide (Stupp regimen) adopted Despite multimodality treatment, recurrence/progression is the rule Universally dismal survival (median OS rarely exceeds months) Benefit of adding bevacizumab in upfront setting unknown Molecularly targeted therapy being tested and developed

105 Pediatric Glioblastoma: Molecularly Different Disease Schwatrzentruber et al, Nature 2012

106 Molecular subgroups of pediatric high grade glioma Gajjar et al, JCO 2015

107