High Grade Glioma

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Dr. Ayush Garg High Grade Glioma

Transcript of High Grade Glioma

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Dr. Ayush Garg

High Grade Glioma

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WHO CLASSIFICATION OF BRAIN TUMORS (2007)

1. Tumors of neuroepithelial tissue2. Tumors of cranial and paraspinal

nerves3. Tumors of meninges4. Lymphomas & haemopoeitic

neoplasms5. Germ cell tumors6. Tumors of sellar region7. Metastatic tumors

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TUMORS OF NEUROEPITHELIAL TISSUE Neuroepithelial cells:progenitors to the CNS neurons and glia

1. Astrocytic tumors2. Oligodendroglial tumors3. Oligoastrocytomas4. Ependymal tumors5. Choroid plexus tumors6. Other neuroepithelial tumours 7. Neuronal & mixed neuronal glial tumors8. Tumours of pineal region9. Embryonal tumors

GLIOMAS

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CBTRUS Statistical Report: Primary Brain and Central Nervous System

Tumors Diagnosed in the United States in 2006-2010

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GRADING OF ASTROCYTIC TUMORS (WHO 2007) Commonest – 1/3 of primary brain tumorsAstrocytic Tumours I II III I V

SEGA *

Pilocytic astrocytoma *Pilomyxoid astrocytoma *

Diffuse astrocytoma *PXA *

Anaplastic astrocytoma *GBM *Giant cellGBM *Gliosarcoma *

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Astrocytic Tumors (WHO 2007)

WHO Age SiteAnaplastic Astro (Gr.III) 5th decade Cerebral hem, brainstemGBM (Gr.IV) 6th decade Cerebral hemisphere

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Challenge to Neuro-Oncologists

unique biology : Widely invasive / infiltrative Inherent tendency to recur Malignant progression on

recurrence Resistance to conventional forms

of therapy - RT & CT

Biology of Gliomas

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WHO 2007 classification - Mainstay of Diagnosis

• Routine histopathology supplemented with IHC

Type of glioma– Astrocytic / oligo / oligoastro / ependymal

Grading of glioma– Astrocytic tumors : grade I to IV– Oligo / oligoastrocytic tumors : grade II & III– Ependymal tumors : grade I to III

• MIB-1 proliferation index– Very important supplement to histopathological

diagnosis in CNS tumors– Very good guide to surgeons regarding patient

management

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Feature Anaplastic astro Gr III

GBM Gr IV

High cellularity and nuclear atypia

+ +

Mitosis + +

Necrosis - +

Microvascular proliferation (multi layered blood vessels)

- +

*GBM cellular heterogeneity - Multi nucleated cells, gemistocytes, granular cells, lipidized cells

** Prominent MV proliferation &/or necrosis

Histopathological Features of Astrocytic Tumors

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Immunohistochemical Features • GFAP : +ve (degree of cytoplasmic positivity highly

variable- related to grade)• S-100 : +ve (less specific glial marker; but +ve even

in gliomas in which GFAP is –ve / equivocal)• CK : –ve (false +ve with AE1/AE3 cocktail; not with CAM 5.2)• EMA : –ve

Proliferation Index MIB-1 labeling index correlates with grade

– Grade I : 1-2%– Grade II: <5%– Grade III: 5-10%– Grade IV: >10-20%

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• Increased cellularity compared to grade II

• Nuclear atypia, pleomorphism

Anaplastic Astrocytoma Grade III

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Increased cellularity & pleomorphism

Multinucleated Giant cells

Classical GBM Gr.IV

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Mitosis

Large ischemic necrosisPseudopallisading

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Variants of GBM

Giant cell

Gliosarcoma

Small cell

GBM with oligodendroglial differntiation

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GLIOBLASTOMA MULTIFORME

• Most common & most aggressive subtype of Glioma• Typical symptoms: Headache Cognitive changes Seizures Focal neurological deficits-weakness• MRI - ring-enhancing lesion surrounding central area of

necrosis on T1 weighted imaging- significant FLAIR hyperintensity surrounding the lesion

• Most cases- grow inexorably- finally refractory to all T/t• Recent data- 5-yr survival of almost 30% in patients with

favourable prognostic factors (age< 50 yrs & high PS)

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GLIOBLASTOMA MULTIFORME• 75% of all high grade gliomas• HP features- nuclear atypia, mitotic activity, vascular proliferation and

necrosis- any 3 of these Psuedopallisading necrosis a histologic hallmark• Typically diffusely infiltrative• Prognosis poor - median survival approx. 1 year• Predictors of Survival: Pre T/t patient & tumour character Age at diagnosis Tumor histology KPS Tumor location- frontal lobe tumours improved surv Extent of surgical resection Duration of neurologic symptoms Radiographic response to treatment

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Oligodendroglial tumors

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WHO Grading (2007)

• Anaplastic oligodendroglioma: Grade III

De novo Progression from Grade II oligo

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Clinical FeaturesFeatures Oligo III

Incidence 1.2% of all primary brain tumors (20 – 35%) of all oligo tumors are grade III.

Age range Middle age adults. Distinctly rare in children.

Peak age 45 – 50 yrs (approx 7-8 yrs older than pts with grade II oligo)

Sex Male predominanceLocation Cerebral hemispheres

-Frontal lobe commonest (50-65%)-Parietal & temporal lobes-Rare sites: cerebellum, basal ganglia, brainstem, spinal cord

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Histopathological features of Oligodendroglioma Grade III

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Increased cellularity with endothelial proliferation

Endothelial proliferation with glomeruloid formation

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High MIB

Frequent Mitosis

Necrosis

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Oligoastrocytoma

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Oligoastrocytoma• Diffusely infiltrating gliomas.• Admixture of tumor cells with oligodendroglial

and astrocytic differentiation• Two variants:

– Biphasic or compact variant : Oligo and astro components in geographically distinct zones.

– Intermingled or diffuse variant : both oligo and astro components intimately intermixed.

• Clinical features & radiology :– overlap with pure astro and pure oligo tumors

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Anaplastic oligoastrocytoma grade III

? Oligoastrocytoma grade IV / GBM with

oligodendroglioma component (GBMO).

WHO grading (2007)

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Feature Grade III Oligoastro

Grade IV Oligoastro/GBMO

Cellularity & cytological atypia

Moderate to severe Moderate to severe

Mitosis Frequent Frequent

Endothelial prolif. Present Present

Necrosis Absent Present

Mean survival time 2 – 4 yrs ~ 22 mths

WHO Grading

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p53 1p 19qATRX

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• New age tool in patient care management• Markers related to genetic/epigenetic alterations –

– deletions, amplifications, translocations, mutations, promoter methylation• Diagnostic biomarkers

– Help in classification of tumor with ambiguous histological features.– Allow for clinically useful subdivision of tumors within a given histological

tumor type.• Prognostic biomarkers

– Correlate with disease free & overall survival.– Provide information beyond that obtained by already established

prognostic parameters.• Predictive biomarkers

– Provide information on response to given therapy which will help to stratify patients into distinct therapeutic groups to allow for optimal t/t.

Molecular biomarkers

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Molecular pathology • Understand the role of molecular genetic alterations in the initiation and

progression of gliomas • Identify different pathways of gliomagenesis - result of multiple complex

genetic alterations that accumulate with tumor progression

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1p/19q codeletion

IDH1 mutation

ATRX mutation

Markers for integrated diagnosis of diffuse gliomas

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1. Combined 1p/19q deletion Diagnostic

Prognostic

Predictive

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1p/19q loss in Oligodendrogliomas

Combined loss of 1p & 19q – characteristic mol sign of oligodendroglial tumors (Gr II & III)

60 to 90% of oligodendrogliomas 40 to 60% of oligoastrocytoma 5 to 15% of Astrocytomas

Loss of 1p & 19q - favourable prognostic marker Longer survival (OS & PFS) Chemosensitivity (PCV & TMZ)

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IDH1 Mutation

Diagnostic Prognostic

• Isocitrate dehydrogenase 1 (cytosol) and 2 (mitochondrial)

• Participates in the citric acid cycle, NADP+ dependant

• IDH1: hot spot mutation at position 395 (amino acid residue 132)– Mostly G A

(substitution of Arg His)

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IDH1 mutation

• Early lesions in gliomas • Site : codon 132 of IDH1and codon 172 of

IDH2• Majority grade II and III gliomas, and 20

GBMs, share IDH mutations• USE Diagnostic value

-positively identifying diffuse gliomas

- distinguishing them from reactive gliosis Association with a better prognosis

IDH1 gene on chromosome 2q33.3 encodes for isocitrate dehydrogenase . Catalyzes NADPH production via oxidative decarboxylation of isocitrate to alpha-KG in the Krebs citric acid cycle

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Alpha Thalassemia/Mental Retardation Syndrome X-linked

gene (ATRX)

Diagnostic ? Prognostic

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ATRX gene• ATRX (α thalassemia/mental retardation syndrome X-

linked) and its binding partner DAXX (death-associated protein 6) are central components of a chromatin remodeling complex

• Normal functions– Chromatin remodelling and nucleosome assembly– Regulates incorporation of histone H3.3 into telomeric

chromatin– Plays crucial role in normal telomere homeostasis

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New WHO guidelines: Diffuse gliomas

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Other Important molecular bio-markers in gliomas not yet integrated into classification

Markers only of diagnostic use Tp53 gene mutation EGFR amplification / EGFR vIII mutant CDKN2A deletion / p16 loss LOH 10q / PTEN deletion BRAF Duplication/Fusion BRAF V600E mutation

Marker only of prognostic / predictive use MGMT promoter methylation TERT mutation

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Glioblastoma• Histological featuresMolecular profile – Primary GBMs

• No 1p/19q deletion• No IDH1 mutation• No ATRX loss• Combination of 7p gain and 10q loss• EGFR amplification

GBM with ATRX loss and IDH mutation (15-18%) – possibly Secondary GBMs

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MGMT (O6 – Methyl Guanine-DNA-Methyl Transferase) Promoter

Methylation

Prognostic and Predictive Molecular Marker

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• MGMT (O6 – Methyl Guanine-DNA-Methyl Transferase)– DNA repair enzyme – Gene located on Chr 10q26– Inhibits killing of tumor cells by alkylating agents

(chemotherapeutic drugs)

• Alkylating agents Tumor cell death

Alkylates O6 position of guanine Crosslinks adjacent

DNA strands

MGMT

Reverts alkyl gp. addition

No lethal cross links

No tumor cell killing

DNA

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New Prognostic Marker

TERT Mutation

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TERT mutations• Recurrent mutations in promoter region of telomerase reverse

transcriptase (TERT)• Gene encoding catalytic subunit of telomerase• Two most common mutations - C228T, C250T

– Associated with marked upregulation of TERT expression

C228T mutationC250T mutation

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Principles of Brain Imaging

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Treatment

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GLIOBLASTOMA MULTIFORMESurgery• A critical component of T/t• Survival: extensive resection> partial resection>surgical decompression• Devaux et al (1993)- Resection & RT- med. surv.-50.6 wks• Laws et al (2003) - Biopsy & RT- med. surv.-33.0 wks• Lacroix et al (2001) - Resection of at least 98% tumour tissue increased med.

surv. (13 vs 8.8 months) • Maximal surgical resection- currently accepted standard of care esp. for patients

<65 yrs• Larger resection-increased diagnostic accuracy and tissue for molecular

profiling- may prognosticate and guide T/t• Gliomas- “ïnfiltrating propensities” without clear demarcation from normal

tissues• Include T/t with potential to target focal disease and microscopic tumour cells

throughout brain

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GLIOBLASTOMA MULTIFORMERadiotherapy• Diffusely infiltrate brain beyond gross tumour & recur locally• RT- a critical component - focus T/t to areas of highest risk• In current form - GTV and margin of several cms• Benefit clearly seen since 1970s. Use dates back to 1925• Shapiro and Young (1976)- CT vs CT+RT. RT 45Gy+15Gy RT+CT(BCNU+VCR)- med. surv.- 44.5 wks CT-med. surv - 30 wks • Coop. Gr. Trials: Improved surv. for RT ± nitrosurea - med surv. - 9-12 months vs. half

of this when RT excluded• Radiosurgery- interest in past - abandoned after negative trials• Current standard - total of appr. 60Gy / 30#• Different total dose, fractionation and delivery methods tried• Ext. beam RT+Temozolamide & adjuvant Temozolamide

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ChemotherapyAgents

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GLIOBLASTOMA MULTIFORME• Chemotherapy• Stupp trial randomized 573 patients with newly diagnosed glioblastoma to

either RT alone (total 60 Gy in 30 fractions; control arm) or RT + TMZ (total 60 Gy in 30 fractions; experimental arm). Patients on the experimental arm received temozolomide daily during RT at a dose of 75 mg/m2, followed by monthly temozolomide at a dose of 150 to 200 mg/m2 on a 5 of every 28 days schedule for 6 cycles.

• Patients randomized to the experimental arm had a median survival of 14.6 months as compared to 12.1 months for the control arm. The 2-year survival of patients treated with radiation therapy plus chemotherapy was 26% as compared to 6% for radiation alone.

• The survival benefit from the addition of temozolomide has now been demonstrated for at least 5 years out from initial treatment and in all clinical prognostic subgroups, including patients aged 60 to 70 years and in RPA classes III through V. Five-year overall survival was 9.8% for patients who received combined temozolomide and radiotherapy as compared to 1.9% for those who received radiotherapy alone.

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• The RTOG recently completed a 1,100-patient, randomized, phase III trial comparing standard adjuvant temozolomide with a dose-dense schedule in newly diagnosed glioblastoma.

• A total of 833 patients were randomized to receive either standard therapy (temozolomide plus radiotherapy followed by 6 to 12 cycles of temozolomide at a dose of 150 to 200 mg/m2 on a 5/28 day schedule) or dose-intense temozolomide (temozolomide plus radiotherapy followed by 6 to 12 cycles of temozolomide at a dose of 150 mg/m2 on a 21/28 day schedule).

• There was no statistical difference between the experimental and standard arms for overall survival (16.6 vs.14.9 months, p = .63) or progression-free survival (5.5 vs. 6.7 months, p = .06), indicating no additional benefit from dose-intense temozolomide.

• The trial prospectively stratified for MGMT methylation status, and no survival benefit with dose-intense therapy was identified in any subgroup. As expected, the dose-intense arm resulted in increased toxicity.

• Thus, at the present time, there is no role for dose-intense temozolomide for newly diagnosed glioblastoma patients.

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• Other chemotherapeutic regimens, such as the combination of CPT-11 and temozolomide, have shown promising results in a phase II trial with an objective response rate of 25% and 6-month progression-free rate of 38%. When tested prospectively in a single-arm RTOG trial, the regimen did not show improved survival.

• Buckner et al. reported on a phase III trial of carmustine with or without cisplatin before and concurrently with radiotherapy and observed increased toxicity but no survival benefit with the addition of cisplatin.

• Two large phase III, randomized clinical trials investigating the addition of bevacizumab to the EORTC/NCIC regimen have completed accrual, and results are pending.

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• Anaplastic Oligodendroglioma/Oligoastrocytoma• Anaplastic oligodendroglioma and oligoastrocytoma are generally

chemosensitive primarily based on high response rates to PCV in several studies.

• Two large randomized trials, described earlier, investigated the use of sequential chemoradiotherapy compared to radiotherapy alone with chemotherapy reserved for salvage in patients with anaplastic oligodendroglioma and oligoastrocytoma.

• With 11-year follow-up, no difference in survival was found for the entire cohort, but for the codeleted patients, there was a near-doubling of survival, establishing chemoradiotherapy as a standard for this subset.

• Because of the significant toxicity associated with PCV, many clinicians now use temozolomide, which is much better tolerated.

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GLIOBLASTOMA MULTIFORMEEarly Brain Tumour Study Group Studies

Dose Response to Radiation based on 3 BTSG studies (Walker et al 1979)

Med. Surv.(weeks) P-valueBTSG 6901( Walker et al, 1978)Best supportive care 14BCNU (Carmustine) 18.5 0.119Radiation 35 0.001Radiation+BCNU 34.5 0.001BTSG 7201(Walker et al, (1980)MeCCNU (Semustine) 31Radiation 37 0.003Radiaiton+BCNU 49 <0.001Radiaiton+MeCCNU 43 <0.001

No RT ≤45 Gy 50 Gy 55 Gy 60 GyMed. Surv (wks) 18 13.5 28 36 42

P-value 0.346 <0.001 <0.001 <0.001

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GLIOBLASTOMA MULTIFORMEBrachytherapy for GBM• Retrospective data- technique promising- I-125 improved med. surv. from 17.9

months in RTOG Class III patients to 28 months. Improvement also in Class IV & V (Videtic et al. 1999)

• Prospective studies failed to support this

Med. Surv.(weeks) P-Value

Brain Tumour Cooperative Group (Selker 2002)60.2 Gy 58.5

60.2 Gy+I-125 (60Gy) 68.1 0.101

Princess Margaret (Laperriere et al,1998)50 Gy 57.2

50Gy+I-125 (60Gy) 59.8 0.49

UCSF (Sneed et al, 1998)59.4 Gy+I-125 (60Gy) 76

59.4 Gy+ I-125(60Gy) + Hyperthermia 85 0.02

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GLIOBLASTOMA MULTIFORME

Radiation Volumes:

• Historically margins to cover potential microscopic disease beyond visualised area of disease-typically 2cm around gross tumour

• Better imaging and sophisticated radiation delivery- variation in margin• Partial brain RT is standard - no benefit of WBT in terms of survival and

control (Shibamoto et al, 1990)• 90% recurrence within 2cm of known primary tumour - typically 2-3cm margin • Using oedema to delineate microscopic disease imperfect- imaging that is

more specific to tumour better• UCSF- MRI spectroscopy to define volume (Park et al. 2007)• Univ. Michigan- 11C-methionine PET (Lee et al, 2007)

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GLIOBLASTOMA MULTIFORMERadiation Volumes:• Historically margins to cover potential microscopic disease beyond visualised

area of disease • Typically 2cm around gross tumour• Better imaging and sophisticated radiation delivery-variation in margin

RTOG (old) RTOG (new) EORTC NABTT

Total Dose 46 Gy 46 Gy 60 Gy 46 Gy

Initial Margin 2 cm block 2cm dosimetric to PTV 2-3 cm dosimet. to PTV 1 cm dosimetric to PTV

Initial Vol. Def. T2/FLAIR T2/FLAIR T1+ Contrast T2/FLAIR

Boost + + - +Boost Dose 14Gy 14 Gy 14Gy

Boost Margin 2.5cm block 2.5 cm dosimet. to PTV 1cm dosimetric to PTV

Boost Vol. Def. T1 + Contrast T1+ Contrast T1+ Contrast

IMRT allowed No No No Yes

Final Dose 60Gy 60 Gy 60 Gy 60 Gy

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GLIOBLASTOMA MULTIFORME

Radiation Volumes:

• IMRT as a means to hypofractionate / deliver more dose centrally in some centre

• Preliminary studies- RT over 2-4 weeks without concurrent CT comparable to full 6 weeks T/t (Floyd et al, 2004; Sultanem et al 2004)

• With this RT can be given safely and effectively in a shorter period of time• IMRT using conventional fractionation- incorporated into current studies

including studies by NABTT- uses 5mm margin for CTV and PTV both for initial and boost volume

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GLIOBLASTOMA MULTIFORME

Simulation:

• CT based simulation typically used• Thermoplastic mask and contrast usually given • GBM may progress after postoperative images acquired- contrast used in

simulation may help identify progression following surgery• After CT simulation, fusion of MRI image if available• Critical structures typically included-lenses, eyes, optic nerve, optic chiasm,

pituitary, hypothalamus, cochleas, brainstem

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GLIOBLASTOMA MULTIFORME

Dose Limiting Structures:

• Given poor outcome - tumour coverage often not sacrificed to limit dose to critical structures

• Improv. outcomes & subsets living ≥5yrs- reducing late tox. a concern• Higher doses can be given to these- compromise of tumour coverage not

allowed• Clinical judgement used to exclude these sensitive structures from PTV• May exclude regions where natural barriers precludes microscopic tumour

extension- cerebellum, contralateral hemisphere, directly across from tentorium cerebri & ventricles

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GLIOBLASTOMA MULTIFORME

Dose Limitation to Critical Structures (RTOG 0525 study)

Structure Dose Limit

Optic Chiasm / Optic nerve 54 Gy

Retina 50 Gy

Brainstem 60 Gy

Lens Shielded from direct beam

Cervical Spine Shielded from direct beam

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GLIOBLASTOMA MULTIFORME

Toxicity:

Incidence of radiation necrosis in GBM following 60Gy difficult to determine- estimated to be 5% by extrapolation data

Structure Dose Limit

Likely(>10%) Redness and soreness, hair loss, fatigue, lethargy, temporary aggravation of symptoms- headaches, seizures, weakness

Less likely (<10%)Mental slowing, Ear/ear canal reactions- short term hearing loss, cataracts, behavioural change, nausea, vomiting, pituitary related endocrine changes, severe damage to brain tissue, dizziness, seizures, dry mouth altered taste

Rare but serious(<1%) Optic injury- possibility of blindness, permanent hearing loss, depression

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GLIOBLASTOMA MULTIFORME

GBM in elderly / poor performance patients:

• RT beneficial in elderly - Keime-Guibert et al (2007) RT vs best supportive care- RT improves survival- 81 patients ≥70 yrs- 50Gy or no RT- med. surv. 29.1 wks with RT vs. 16.9 wks with no RT. No CT. Dose scheme may not have had an effect on outcome

• Roa et al (2004)- 100 patients ≥ 60yrs- 60Gy/30# vs 40Gy/15# - med. surv 5.1 mon. vs 5.6 mon. (p=0.57, NS)-no CT used. No diff. med OS

• RT 0525 allows elderly to enrol- presumption that elderly may benefit from aggressive T/t incorporating CT

• Other studies to see if CT can benefit this subset• Chamberlain et al (2007)- TMZ without RT being investigated in elderly• In poor PS patients, KPS <60 - hypofractionated course of RT reasonable (Bauman GS

et al ,1994; Chang EL et al, 2003) - 30Gy/10# or 37.5Gy/15# WBT or focal RT 40-45Gy/15# - to complete T/t early. These patients do poorly with med. surv. 7 months

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GLIOBLASTOMA MULTIFORME

Radiation sensitizers:

• Motexafin Gadolinium (Xcytrin) - previously known as Gadolinium Texaphyrin or Gd-Tex- redox mediator selectively targets tumour cells- generation of reactive oxygen species and fixation of damage by radiation

• Phase I study in GBM - max tolerated dose 5mg/kg/day daily for 2 wks, then 3 times per week till RT completion. TMZ not given (Ford et al 2007)

• Results from a single-arm phase II trial, RTOG 0513, of MGd and conventional therapy in newly diagnosed GBM showed no survival improvement.

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GLIOBLASTOMA MULTIFORME

FOLLOW-UP:

• MRI scan 4 weeks after completion of CT+RT, 2-3 months thereafter• Pseudoprogression- one area of controversy- worsening FLAIR or T1 contrast

soon after RT completion- may resolve if followed long enough rather than changing planned T/t course

• Controversial how to image pseudoprogression and distinguish from tumour progression

• Cause unknown- seen more frequently after using aggressive upfront T/t- acute T/t related changes including blood-brain barrier disruption and oedema

• While FU of GBM, pseudoprogression a D/d

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GLIOBLASTOMA MULTIFORME

RE-IRRADIATION

• Studied both for local and distant recurrence• Often given stereotactically

Study Authors Nos of Pts. Med. Dose in Gy Med. Surv

U.. Michigan Kim et al. 1997 20 36 (30.6-50.4) 9 mo

Germany Vordermark et al.. 2005 14 30. Hypo. Stereo.

Med 5Gy/# 7.9 mo

U. Heidelberg Combs et al. 2005 53 36. Med #-2Gy 1mm mar. stereo 8 mo

U. Wisconsin Tome et al. 2007 99LDR radiation. 0.2 Gy pulses 3 min apart

6 mo 31% surv

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• Recurrence• Single-agent bevacizumab was approved by the FDA in 2009

for the treatment of recurrent glioblastoma. • In a study of 49 glioblastoma patients, Kreisl et al. reported

objective response rate of 35%, 6-month progression-free survival of 29%, 3.7-month median progression-free survival, and 7.2-month median overall survival.

• Similarly, Friedman et al. reported an objective response rate of 28%, 6-month progression-free survival of 43%, median progression-free survival of 4.2 months, and median overall survival of 9.2 months in a total of 85 patients.

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FLOWCHART (NCCN Guidelines)

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• Molecular markers in adult gliomas – well established • Diagnostic use of molecular markers

– To improve the precision of histological diagnosis

– To refine current histomorphology based WHO classification in the future

• Prognostic / predictive markers 1p/19q deletion IDH1 mutation MGMT promoter methylation TERT mutation

Used in routine practice for patient management Very important role of the pathologist

CONCLUSION

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FUTURE DIRECTIONS:

• Better molecular imaging techniques to define and follow areas of disease and better understanding of biology of the disease

• Use of heavy particles- Carbon ions tried in Japan (Mizoe et al., 2007)

• Radioimmunotherapy with I-125-EGFR Mab 425- tried and promising- when added with RT+TMZ, med surv. 20.4 months- (Li et al 2007)

• Future studies to define role of I-125-EGFR Mab 425- and of other radioimmunotherapies

• Agents with radiosensitizing properties- Motexafin Gadolinium currently being studied

• Best “radiosensitizer” to date, TMZ standard in T/t of GBM (Stupp et al. 2005)• Agents to improve efficacy of TMZ being developed and assessed

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High-grade glioma: Where we are and where are we going

• Systemic therapy-most often utilized treatment in recurrent HGG. • Choice of therapy- varies and revolves around re-challenge with

temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV (most frequently used angiogenic inhibitor)

• No clear recommendation regarding prefered agent or combination of agents.

• Prognosis after progression of HGG remains poor, with unmet need to improve therapy.

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THANK YOU