Dr. Ayush Garg

High Grade Glioma

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

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

CBTRUS Statistical Report: Primary Brain and Central Nervous System

Tumors Diagnosed in the United States in 2006-2010

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 *

Astrocytic Tumors (WHO 2007)

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

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

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

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

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%

• Increased cellularity compared to grade II

• Nuclear atypia, pleomorphism

Anaplastic Astrocytoma Grade III

Increased cellularity & pleomorphism

Multinucleated Giant cells

Classical GBM Gr.IV

Mitosis

Large ischemic necrosisPseudopallisading

Variants of GBM

Giant cell

Gliosarcoma

Small cell

GBM with oligodendroglial differntiation

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)

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

Oligodendroglial tumors

WHO Grading (2007)

• Anaplastic oligodendroglioma: Grade III

De novo Progression from Grade II oligo

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

Histopathological features of Oligodendroglioma Grade III

Increased cellularity with endothelial proliferation

Endothelial proliferation with glomeruloid formation

High MIB

Frequent Mitosis

Necrosis

Oligoastrocytoma

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

Anaplastic oligoastrocytoma grade III

? Oligoastrocytoma grade IV / GBM with

oligodendroglioma component (GBMO).

WHO grading (2007)

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

p53 1p 19qATRX

• 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

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

1p/19q codeletion

IDH1 mutation

ATRX mutation

Markers for integrated diagnosis of diffuse gliomas

1. Combined 1p/19q deletion Diagnostic

Prognostic

Predictive

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)

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)

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

Alpha Thalassemia/Mental Retardation Syndrome X-linked

gene (ATRX)

Diagnostic ? Prognostic

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

New WHO guidelines: Diffuse gliomas

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

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

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

Methylation

Prognostic and Predictive Molecular Marker

• 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

New Prognostic Marker

TERT Mutation

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

Principles of Brain Imaging

Treatment

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

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

ChemotherapyAgents

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.

• 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.

• 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.

• 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.

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

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

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)

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

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

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

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

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

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

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

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.

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

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

• 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.

FLOWCHART (NCCN Guidelines)

• 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

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

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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