High grade glioma guidelines.

Written by: Mr Michael Jenkinson, Consultant Neurosurgeon

Agreed by: Merseyside and Cheshire Neuro-oncology CNG, December 2011
For review: 2013

Walton Centre / Clatterbridge Centre for Oncology guidelines for high grade
glioma management
1

Background

High grade gliomas (HGG) account for ~70% of all gliomas and predominantly affect patients between
40-70 years of age. They are diffusely infiltrating tumours, which according to the WHO classification
can be divided into anaplastic astrocytoma (WHO grade III), anaplastic oligodendroglioma (WHO III),
anaplastic oligoastrocytoma (WHO grade III) and glioblastoma multiforme (GBM) (WHO grade IV) (4).
They are commonly located in or near to eloquent brain regions, i.e. motor, language, visuo-spatial
and memory.

These tumours continue to have growth potential, there is no stable tumour and

recurrence tends to be at the site of the original disease. More recently recurrence distant from the
original site has been reported (so called multi-focal recurrence). Death is usually due to recurrence
and disease progression and the optimal treatment of HGG is tailored to individual patients.

1.1

Clinical Features

Features of raised intracranial pressure and focal neurological deficit are the commonest presenting
complaint. Patients may also have partial or generalised seizures and an appropriate antiepileptic
drugs (AED) should be commenced. Focal neurological deficits are more likely to be permanent due
to the infiltrative nature of these tumours, however in some patients these improve with
dexamethasone and surgical resection.

1.2

Conventional and advanced MR imaging

High grade gliomas tend to be hypointense on T1W, with marked peripheral contrast enhancement
with gadolinium. They have a heterogeneous signal on T2W and FLAIR which extends beyond the
margins of the tumour seen on T1 + gadolinium. MR spectoscopy, perfusion and diffusion provide
additional information at baseline assessment and can be used to differentiate gliomas from other
lesions e.g. abscess, meningioma, metastasis.

1.3

Prognosis

Due to their infiltrative nature high grade gliomas are not curable. Prognosis according to pathology
is: anaplastic oligodendrogliomas > anaplastic astrocytoma > glioblastoma.

Anaplastic gliomas

(grade III) have a median progression free survival (PFS) of ~2 years, and a median overall survival
(OS) of ~3 years. Glioblastoma mulitforme (GBM) has a worse prognosis and the median OS is 1214 months, however there are an increasing number of longer term survivors, beyond 2-3 years.
Radiotherapy with concomitant and adjuvant temozolomide (Stupp regime) is now the gold standard
regime for GBM and increases median OS from 12.1 to 14.6 months, and increases 2 year survival
from 10.4% to 26.5% (6). Age, performance status, extent of surgical resection, mini mental score
examination (MMSE) and MGMT status are significant prognostic factors and the EORTC produced
an

online

Page 1 of 6

calculator

that

can

be

used

to

estimate

prognosis

for

individual

patients

High grade glioma guidelines. Written by: Mr Michael Jenkinson, Consultant Neurosurgeon
Agreed by: Merseyside and Cheshire Neuro-oncology CNG, December 2011
For review: 2013

(http://www.eortc.be/tools/gbmcalculator) (2).
associated with worse outcome.

Large tumours and those crossing midline are

Favourable genetic markers include MGMT promoter

hypermethylation (3) and IDH1 mutation (8), however these are not standard tests in most pathology
laboratories.

2.

Management options

2.1

Surgery

Surgical options include biopsy, debulking and macroscopic resection, which provides tissue for
diagnosis, grading, molecular studies and ongoing research. Surgical options depend on clinical
condition, performance status, tumour location, response to dexamethasone and patient choice. The
aim of gross total resection (GTR) is removal of all the contrast enhancing tumour visible on MRI
T1+gadolinium. In addition to providing a diagnosis, GTR and tumour debulking (subtotal resection:
STR) reduce the mass effect, reduce the dexamethasone requirement and may improve neurology
and performance status. The effect of extent of resection (EOR) on OS and PFS is increasingly being
recognised to improve prognosis and subsequent response to adjuvant therapy.
Intra-tumoural carmustine wafers (Gliadel) are a surgical adjunct, which are NICE approved for first
line treatment of HGG.

Wafers are placed in the resection cavity (>90% resection should be

achieved) and the chemotherapy diffuses 2-3 mm into the tumour bed. The offer a modest increase
in median OS of ~2 months (1).
Fluorescence-guided resection (Gliolan) is a new technology that produces detectable fluorescence
within the tumour at resection and has been demonstrated to increase the extent of resection, and
therefore median OS (5).

2.2

Radiotherapy

Adjuvant external beam fractionated radiotherapy aims to prolonged time to inevitable tumour
recurrence and progression, whilst minimising CNS adverse effects such as radiation necrosis and
neuro-toxicity leading to cognitive decline. Three radiotherapy regimes are in common use and are
tailored to individual patients:
a) radical radiotherapy with concomitant temozolomide (Stupp regime) (6)
b) radical radiotherapy alone
c) palliative radiotherapy

2.3

Chemotherapy

Temozolomide is the chemotherapy drug of choice and in certain patients is given concomitantly with
radiotherapy followed by 6 cycles of adjuvant treatment as part of the Stupp regime (6). CCNU is less
effective and is typically used when there is evidence of tumour recurrence or progression, when
there are no further surgical options.

Page 2 of 6

High grade glioma guidelines. Written by: Mr Michael Jenkinson, Consultant Neurosurgeon
Agreed by: Merseyside and Cheshire Neuro-oncology CNG, December 2011
For review: 2013

2.4

Best supportive treatment / palliative care

At initial presentation some patients are not fit enough for adjuvant radiotherapy, therefore biopsy for
tissue diagnosis is not indicated and symptomatic treatment only should be offered. This assumes
that the MRI appearance of the tumour is consistent with a diagnosis of HGG. In addition, following
surgery, some patients do not recover or improve sufficiently to have adjuvant radiotherapy and
symptomatic treatment only should be offered.

2.5

Treatment options at recurrence

High grade gliomas all tend to recur and treatment is tailored to individual patients according to
clinical status, radiological pattern of recurrence and following MDT discussion. Options include:
a) revision surgery +/- Gliadel
b) revision surgery +/- further radiotherapy
nd

c) 2 line chemotherapy with CCNU

d) re-challenge chemotherapy with temozolomide
e) stereotactic radiosurgery (SRS) in highly selected cases
f) participation in clinical trials

3.

WCFT / COO management guidelines (see flowchart)

3.1

At presentation
Baseline conventional MRI brain
Patient discussed pre-operatively at neuroscience MDT
Commence AED if patient has seizures consider neurology advice / input if refractory
Discuss management aims: maintain quality of life, minimise tumour volume, stabilise disease
Discuss management options:
o

Best supportive treatment / palliative care

Biopsy

Resection (GTR, STR)

It is important to emphasis that these tumours are malignant and not curable

3.2

Surgery
Surgical resection should be the first treatment option the goal is maximal safe resection of
signal abnormality defined on T1+gad. The post-operative MRI should be obtained within 72
hours and include a volume T1+gad to determine EOR and volume of residual disease as per
the RANO criteria for measuring response to treatment (7).
Awake craniotomy +/- neurophysiology monitoring should be considered for eloquent tumours

Page 3 of 6

High grade glioma guidelines. Written by: Mr Michael Jenkinson, Consultant Neurosurgeon
Agreed by: Merseyside and Cheshire Neuro-oncology CNG, December 2011
For review: 2013

When resection is not feasible due to location / extension / co-morbidity / patient choice
biopsy for histological conformation should be obtained
Re-resection should be considered at recurrence according to clinical status, initial response
to treatment and radiological appearance
Gliadel is currently reserved for patients aged 50 years old who have surgically respectable
recurrent tumour > 6 months following completion of radiotherapy for HGG (both grade III and
IV)
Gliolan is currently only available to patients enrolled in the GALA-5 clinical trial (WCFT is an
approved investigating site)

3.3

Radiotherapy
Stupp regime is offered to patients <70 years old and performance status 0 -1
Radical radiotherapy is offered to patients >70 years old and performance status 0 -1
Palliative radiotherapy is offered to patients of performance status 2

3.4

Chemotherapy
Temozolomide is given as part of Stupp regime and as a re-challenge at recurrence
CCNU is 2

3.5

nd

line chemotherapy used at recurrence

Clinical and radiological follow-up

To minimise duplication of clinic appointments and MRI scans the following is proposed:
MRI is the modality of choice for follow up and should include T1 +/- gad, T2, FLAIR
MRI schedule and location:
o

Pre-surgery WCFT / referring hospital as per radiology CNG agreement

Post-surgery (within 72 hours only in those undergoing GTR or STR) - WCFT

Pre-RT planning - CCO
Post-RT (1 month post-RT, pre-adjuvant chemo) - CCO
Mid-adjuvant chemo (after 3 cycles) - CCO
Post-adjuvant chemo (after 6 cycles) - CCO
Every 6 months from 12 months-24 months - CCO
Any routine MRI images after 24 months - CCO / Walton

Perfusion

MRI

can

be

useful

for

differentiating

between

tumour

recurrence,

pseudoprogression and radiation necrosis this can be performed at WCFT

Clinical follow-up during radiotherapy is by the clinical oncologist
Follow up after completion of radiotherapy can be by the oncologist and / or neurosurgeon
either alone, in conjunction or alternatively. All effort should be made to avoid duplication of
OPD and MRI attendences

Page 4 of 6

High grade glioma guidelines. Written by: Mr Michael Jenkinson, Consultant Neurosurgeon
Agreed by: Merseyside and Cheshire Neuro-oncology CNG, December 2011
For review: 2013

Patients undergoing further surgery +/- Gliadel at recurrence should be follow-up by the
neurosurgeons until recurrence then transferred back to the clinical oncologist for possible
chemotherapy
Once all active treatment options have been exhausted follow-up should be transferred to
palliative care team

4.

References

1.

Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S,
Mohr G, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled
delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymerbrain Tumor Treatment Group. Lancet 345:1008-1012, 1995.
Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, Eisenhauer E,
Belanger K, Brandes AA, Allgeier A, Lacombe D, Stupp R: Nomograms for predicting survival
of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and
NCIC trial 26981-22981/CE.3. Lancet Oncol 9:29-38, 2008.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA,
Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp
R: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med
352:997-1003, 2005.
Louis DN, Ohgaki H, Wiestler OD, Cavanee WK: WHO Classification of Tumours of the
Centre Nervous System. 2007.
Pichlmeier U, Bink A, Schackert G, Stummer W: Resection and survival in glioblastoma
multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol
10:1025-1034, 2008.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K,
Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier
A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant
and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J,
Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp
R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM: Updated response
assessment criteria for high-grade gliomas: response assessment in neuro-oncology working
group. J Clin Oncol 28:1963-1972, 2010.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I,
Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW,
Velculescu VE, Vogelstein B, Bigner DD: IDH1 and IDH2 mutations in gliomas. N Engl J Med
360:765-773, 2009.

2.

3.

4.
5.

6.

7.

8.

Page 5 of 6

High grade glioma guidelines. Written by: Mr Michael Jenkinson, Consultant Neurosurgeon
Agreed by: Merseyside and Cheshire Neuro-oncology CNG, December 2011
For review: 2013

The Liverpool high grade glioma pathway

HGG have rapid growth characteristics
Age, performance status, extent of resection,
dexamethasone requirement, MGMT and IHD-1
status are significant prognostic factors
Death is usually due to tumour progression and
recurrence
The goal of management is to maintain quality of
life and stabilise the tumour

Biopsy

For gliomatosis
Patient choice
Best supportive treatment
Palliative care team input

Resection

Gross total resection (GTR)

Subtotal resection (STR)

assess EOR

Neurophysiology monitoring and

awake craniotomy for eloquent
tumours

Fluorescence (Gliolan) guided

resection for tumours amenable to
GTR

No

Radiotherapy only:
Radical or palliative

ADJUVANT OPTIONS

XRT + temozolomide

FOLLOW-UP

Neurosurgery / neuro-oncology clinic

MRI follow-up

Page 6 of 6

No role for prophylactic

AED

DIAGNOSIS

Chemo-radiotherapy
Radiotherapy

No

ECOG 0-1
Age <70

GBM
Yes

Chemotherapy
If oligodendroglial and /
or large to avoid RTinduced neuro-toxicity

Start AED

Seizures?

Post-op MRI within 72 hours to

Anaplastic astrocytoma
Anaplastic oligodendorlgial

Yes

SURGICAL OPTIONS

Palliative

New radiological diagnosis of high grade

glioma
Baseline MRI
Consent for tumour bank
Options: biopsy, resection, palliative