Current Management of GBM
Nishantha Gunasekera
Neurosurgery, Waikato
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“ better a living problem than a dead certainty ”
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Epidemiology
 WHO estimates- 100 different types of
brain tumours
 22 500 new cases –malignant primaries
(US ’07)
 Annual incidence of malignant gliomas
5/100000
 GBM: 60-70%
 Anaplastic astros: 10-15%
 Anaplastic oligos/oligoastros: 10%
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THE most common primary brain tumour
 Biologically aggressive
 Mean age at presentation 56-64 yr
 Median survival 12-15 months
 Presents unique treatment challenges
We Can do something positive for most
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 40% commoner in men
 Twice as more in whites than non whites
 The only established risk factor is ionising
radiation
 Head injury, n-nitroso compounds in food,
electromagnetic fields????
 IgE ? protective
 5% have family history
 NF 1,2 ; Li- Fraumeni syn (p53); Turcot’s
 GLIOGENE – an international consortium
 (to study familial gliomas)
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Challenges
 The variably disrupted blood-brain barrier
complicating drug delivery
 Tumour capillary leakage – oedema, ICP
 Limited response to therapy
 Neurotoxicity of treatment
 Molecular pathology is complex – but
important recent advances have been made
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 Localisation of tumours in the brain
 Intrinsic resistance of tumour to
conventional therapy
 Limited capacity of the brain to repair itself
 The spread of malignant cells into brain
parenchyma
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Predictors of outcome
 Patient age (18 month survival)
 <40y - 50%
 40-60 - 20%
 >60 - 10%
 Histological features
 median survival 10 months for “classic GBMs ’’
 Performance status (18 month survival)
 KPS>70 34%
 KPS<60 13%
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Pathophysiology
 p53 mutation- sets the stage for malignant
transformation
 Allelic loss of ch17p- malignant progression
 Many growth factors/receptors are
over expressed
 PDGF (platelet)
 FGF (fibroblast)
 VEGF (vascular endothelial)
 EGFR (epidermal)
 Progression to WHO Gr II is associated with
 Increased cellularity
 Mitotic activity 9

 GBM is characterised by
 Dense cellularity
 High proliferation indices (Ki67-protein marker of prolif.)
 Vascular endothelial proliferation
 Focal necrosis
 Source of mitogenesis is deregulation of
the p16-cdk4-cyclin D1-pRb pathway
 Ch 10p loss is a frequent finding (60-95%)
 1p19q deletion may indicate better
prognosis- (oligo. component)
 Various subsets of GBM exist depending
on the molecular genetics 10

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Histology
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Spread
 Tracking through white matter
 Corpus callosum
 Cerebral peduncles – midbrain
 Internal capsule – encroach basal ganglion t. Into
centrum semiovale
 Uncinate fasciculus – simultaneous frontal and
temporal
 Interthalamic adhesions – bilateral thalamic gliomas
 CSF pathways
 10-25% frequency of meningeal and ventricular
seeding
 V. rarely systemic
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Clinical features
 Due to raised ICP
 Progressive focal deficits
 Stroke in evolution!!
 Headache
 With or without raised ICP
 Worse in the morning – hypoventilation, co2
 relieved by vomiting - ? Hyperventilation
 77% similar to tension h/a; 9% like a migraine
 Only 8% had “classic tumour headache’’
 Siezures (AOE)
 Mental status changes 16

Investigations
 CT contrast / non contrast
 MRI / fMRI/ MR spectroscopy
 Stealth imaging (CT/MRI)
 Tractography
 Intra-operative brain mapping
(for awake surgery)
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c+ct
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mri
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fmri
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mri spectroscopy
n acytyl aspartate peak = infection
choline peak = tumour
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tractography
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intrapoerative mapping
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Treatment
 Treatment has evolved to include
1. Maximum safe extent of resection
2. Fractionated radiotherapy to tumour bed
3. Alkylating chemotherapy (nitrosoureas:
BCNU)
 based on trials by BTSG (brain tumour study group)
and RTOG (radiation therapy oncology group)
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Treatment issues
 Siezures (levetiracetam does not induce P450)
 Peritumoural oedema (VEGFR inhibitors)
 Venous thromboembolism (20-30%, IVC filters,
anticoagulation)
 Cognitive dysfunction
 Steroid associated probs.
(Cushings, P. jiroveci etc. etc.)
 Abulia (lack of will or initiative) - ? methylphenidate
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 Value of total or near total resection still is
debated but...
 Data from BTSG suggests large volume
resection has a better outcome...
 Value of adjuvant chemotherapy has been
evaluated by meta-analyses (Fine et al,
Stewart et al)
 Modest improvement in 1-2 y survival rates
(5-6% and 4-5% respectively)
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 Glioma Outcome Project data ‘05 (560 newly
diagnosed GBM- 58 community and university centres
involved)
 all patients underwent surgery
 87% received radiotherapy
 88% received anticonvulsants
 54 % received chemo
 29% used alternative meds
15% enrolled in clinical trials
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 These studies clearly demonstrated a benefit
for chemotherapy (that is, TMZ) in the initial
treatment of patients with GBM
 Improvement in median (14.6 compared with 12
months) and 2-year survival (27 compared
with 10%) in patients receiving or not receiving
TMZ.
Consequently, this treatment regimen (TMZ given
concurrently with radiotherapy, followed by six monthly
cycles of TMZ) has become the new standard of care for
patients with newly diagnosed GBM.
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Surgery
 Cytoreductive
 Extent of tumour removal and the volume of
residual tumour on post op imaging have
a significant effect on time to tumour
progression and median survival
 Mass effect reduction
 CANNOT be cured with surgery.. can it?
 Prolong quality of survival
 In the elderly (>65y), the benefit by surgery is
modest (median survival 17w after biopsy, 30 w after surgery : +
XRT)
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 Partial resection of GBMs carries a
significant risk of post op haemorrhage,
oedema with risk of herniation
 Benefit of subtotal resection is deemed
dubious
 Surgical excision should be only considered
when the goal of gross total resection is
feasible
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 The following are usually not surgical
candidates
 Extensive dominant lobe GBM
 Lesions with bilateral involvement (butterfly)
 Deep lesions (brain stem, capsule)
 The very elderly
 Patients with poor Karnofsky scores
 In
general the neurologic condition on steroids is as
good as its going to get- surgery rarely improves this
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Surgical Toys
 Neuronavigation
 Offline
 Realtime (brain suite- intraopeative MRI)
 Fluorescence guided
 Intraoperative mapping
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Brain Suite
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Stereotactic Biopsy
 May underestimate by 25%
 Located in deep areas
 Small T. with minimal mass effect
 Patients with poor medical conditions
 Equivocal clinical diagnosis ( lymphoma!)
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 Stereotactic
 Frame based
 Frameless- stealth
 Free hand
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Reoperation for recurrence
 Less than 10% recur away from the original
site
 Reoperation extends survival by an
additional 36 weeks
 Duration of high quality survival was 10
weeks
 Predictors of good quality of survival after
reoperation include
Age, time from 1st to 2nd surgery, Karnofsky
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 Morbidity is higher (5-18%)
 Infection rate is > X3
 Wound dehiscence more
 Neurological deficits more
 Surgical techniques differ
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Radiation
 Usual dose of XRT is 50-60 Gy – whole
brain radiation has not been shown to
increase the median survival compared to
focal XRT but the risks of side effects is
greater
 Brachytherapy has not shown no significant
benefit as an adjunct to EBRT
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Chemotherapy
 All current agents have no more than
30-40% response rate
 Carmustine and cisplatinum have been the
primary agents
 Temazolamide
 An oral alkylating agent
 Initial FDA approval for relapse or progression
of anaplastic astros. while on a nitrosourea
containing regimen
 Now also used for newly diagnosed GBM and
AA and progressive low grade gliomas
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Chemotherapy
 GLIADEL wafers
 Carmustine 7.7mg in 200mg prolifeprosan 20
hydrophobic polymer carrier (wafer)
 Following T. removal upto 8 wafers are applied
to the resection bed (US$12500 for 8)
 Drug is released over 2-3 wks
 Exposes the tumour to 113 times the conc. of
BCNU achieved by systemic admin.
 Approved by FDA for recurrent GBM
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Drug
Resistance
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New
Therapies
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What next?
 can we prevent?
 can we screen?
 can we immunize?
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