Glioblastoma Tien 2011

8/6/2019 Glioblastoma Tien 2011

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Journal club May 4th 2011


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Glioblastoma Multiforme Epidemiology Pathology Imaging

Radiation Technique Chemotherapy

FET-PET Article review: Red Journal 2011 (Piroth et al)

Prognostic value of18F-fluoroethyl-L-tyrosine PET Post surgery and chemoradiotherapy

Article review: Green Journal 2011 (Piroth et al) Prognostic impact of18F-fluoroethyl-L-tyrosine PET scan Immediately Post-op,pre-chemoradiotherapy

Article review: Green Journal 2011 (Niyazi et al) Value of18F-fluoroethyl-L-tyrosine PET in radiotherapy planning


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World Health OrganizationGrading System

of gliomas

Grade 1 = JPA Grade 2 = fibrillary astrocytoma

Grade 3 = anaplastic astrocytoma

Grade 4 = glioblastoma multiforme (GBM)


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Malignant gliomas are the most commonprimary CNS tumours in adults

Breakdown of adult primary CNS tumours 30% meningioma 20% GBM

10% pituitary

10% nerve sheath

5% low grade glioma


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Incidence in population (Taken from Cancer CouncilVictoria) 6 new cases of CNS primary tumour per 100,000 per year

1-2 cases ofGBM per 100,000 per year 50 + cases inVictoria annually

Risk Factors Sex: male Age: highest incidence 65 to 84 years of age

Lower grade astrocytoma transformation Genetic disorders

Neurofibromatosis,Tuberous sclerosis,Von Hippel-Lindau disease,Li-Fraumeni syndrome,Turcot syndrome


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New onset headaches more than 30% ofpatients

New onset seizures 20% to 30% patients Neurological dysfunction

Vision, Motor function, Sensation Cognitive changes

Memory loss Personality changes Behavioral changes Decreased conscious state


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EORTC-NCIC trial (Lancet Oncol2009)

Randomisedphase III trial with 5 years of followup

573 patients recruited between 2000 2002

286 received RT alone

287 received RT and temozolomide

Results Statistically significant benefits of adjuvant

temozolomide with radiotherapy vs radiotherapy alone,which lasted throughout 5 years of followup


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EORTC-NCIC trial Results at 5 years

97% of RT alone and 89% of RT and chemo died

SURVIVAL

RT + Chemo95% CI SURVIVAL

RT Alone95% CI

2 years 27.2% 22.2 32.5 10.9% 7.6 14.8

3 years 16.0% 12.0 20.6 4.4% 2.4 7.2

4 years 12.1% 8.5 16.4 3.0% 1.4 5.7

5 years 9.8% 6.4 1 4.0 1.9% 0.6 4.4


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RPA r c rsiv partiti i a alysisKPS Kar fsky p rf r a c stat s (< r ir s sp cial

car , r al activity it ff rt, 1 r al)


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Poor prognosis despite intensive efforts to improvetreatment strategies

Median survival of 12 14 months

Further analysis ofEORTC-NCIC trial MGMT gene promoter methylation was the strongestpredictor for outcome and benefit from temozolomide.

Age,performance status, extent of resection and MMSEwere suggested as eligibility or stratification factors

StuppR, MasonWP, van den Bent MJ,et al. Radiotherapy plus concomitant andadjuvant temozolomide for glioblastoma.N Engl J Med2005;352:987-996StuppR, Hegi ME,MasonWP,et al. Effects of radiotherapy with concomitant andadjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a

randomisedphase III study: 5-year analysis of the EORTC-NCIC trial.Lancet Oncol

2009;10:459-466


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World Health OrganizationGrading System

of gliomas

Grade 1 = JPA Grade 2 = fibrillary astrocytoma

Grade 3 = anaplastic astrocytoma

Grade 4 = glioblastoma multiforme (GBM)


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AstrocytomaGrading(AMEN)

Nuclear atypia

Mitoses Endothelial

proliferation

Necrosis

Histology


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Diagnostic gold standard = MRI

Use T1 pre and post gadolinium,T2,FLAIR

Gadolinium enhancement = BBB breakdown GBM

Rim enhancing, central necrosis, irregular borders,mass effect


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Current standard of care for patients betweenages 18 and 70 is based upon EORTC trial byStupp et al.1. Surgery (maximal safe debulking)2. Adjuvant external beam radiotherapy plus

simultaneous and sequential temozolomide Keime-Guibert et al

Randomized 85patients >70y age to radiotherapy orsupportive care only Modest improvements in survival without reducing

quality of life. Median survival 29.1 weeks vs 16.9 weeks


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Fractionated EBRT

60Gy in 30# over 6weeks (EORTC-NCIC)

40Gy in 15# for patients

60years and

KPS 50

3DCRT or IMRT

Dose homogeneity,hot spots (less with 3DCRT)

Sparing of critical structures (better with IMRT)

Fusion ofplanning CT with MRI (post-opMRbetter than pre-op)

RoaW,Brasher PM,BaumanG, et al.Abbreviated course of radiation therapy in older patients withglioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004;22:1583-1588.


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General guidelines for target volumes

GTV1 = T1 enhancement and T2 FLAIR

Boost:GTV2 = T1 enhancement CTV =GTVplus 2cm margin

PTV = CTVplus 0.3 0.5cm margin

May need to individualise tumour volume basedon propensity to infiltrate, follow white mattertracts (int capsule and corpus callosum)


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As per EORTC-NCIC trial

Temozolomide

Oral alkylating agent Concurrent daily (75mg/m2/day) for duration of

RT

Adjuvant (150200 mg/m2/day 5 days) q4 weeks 6 month.


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Gliomas

Have increased expression of amino acid

transporters Amino acid uptake in gliomas is primarily

independent of blood-brain barrier disruption inMRI


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Molecular imaging w/ PET assesses biologicalfunction

18F-fluoroethyltyrosine (FET)

Radiolabelled amino acid Particularly attractive for imaging brain tumours

High uptake in tumour tissue

Low uptake in surrounding brain

Better contrast than FDG (glucose)

High in-vivo stability vs carbon eg 11C-methionine Fast brain and tumour uptake characteristics Low accumulation in non-tumour tissue Ease of synthesis


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Broadly 2 potential uses for FET-PET scanning

1. PLANNING Post-surgery to better contour and delineateGTV

and CTV for radiotherapy

2. PROGNOSIS

Post-surgery and chemoradiotherapy to act as aprognostic tool


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Currently use CT & MRI for RT planning

Especially after surgery,persistent tumour is

often indistinguishable from reparativechanges

True extension of remaining tumour may beunder or overestimated

Aim to find an accurate and reliabledefinition of the extent of viable tissue


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MRI drawbacks

Phenomenon ofpseudoprogression

Transient BBB changes after treatment causeconsecutive contrast enhancement

Estimated 20 47% of cases and can lead toovertreatment

Difficulty in distinguishing tumour and treatmenteffects

Lustig RA,Seiferheld W,Berkey B, et al. Imaging responsein malignant glioma, RTOG 90-06.Am J Clin Oncol 2007;30:

3237.


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1. Red Journal Investigating the use ofFET-PET

after all definitive treatment

As a prognostic tool

2. Green Journal Investigating the use ofFET-

PET after surgery but prior to chemoRT


As a RT planning tool


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1. Red Journal Investigating the use ofFET-PET

after all definitive treatment

As a prognostic tool2. Green Journal Investigating the use ofFET-PET after surgery but prior to chemoRT


As a RT planning tool


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22 patients treated by surgery andchemoradiotherapy

Median age 56 (range 36 73) 9 gross total resection, 13 partial resections Planning CT within 11 20 days postop

17patients received IMRT 60Gy to PTV1 plus boost to PTV2 to 72Gy 5patients had 3D conformal RT

60Gy


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Three FET-PET scans performed per patient

1. Before chemoradiotherapy

2. 7-10 days after

3. 6-8 weeks after

Early treatment response was defined as a

decrease in TBR (tumour vs brain ratio) of 10% There were 16 early responders vs 6 non-

responders

Mean follow-up 10.2 months (3 22)


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Results Median overall and disease free survival of allpatients 14.8 and 7.8 months

When comparing early PET responders:Early PETrespondersN = 16

Non-PETrespondersN = 6

Disease free survivalp< 0.01

10.3 months 5.8 months

Overall survivalP < 0.001

Not reached 9.3 months


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Conclusions FET-PET is a sensitive tool to predict treatment

response in patients with glioblastomas at anearly stage after chemoradiotherapy

Discussion points The level of significance was highest when the

TBR was used as a parameter

TBRmean 2.4 was indicative of median DFS

FET-PET could be used to differentiate tumourrecurrence from radionecrosis if MRI inconclusive


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44 patients withGBM

Recruited between 2005 and 2010 16male, 28 female Mean age 57 years (age 33-78) Surgical resections

17 had gross total resection

24 had partial resection CT simulation and FET-PET and MRI within 11-20 days

of surgery Had chemoradiotherapy (60Gy to PTV1, although

some had boost to 72Gy to PTV2 - area with increased

FET uptake)


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Had FET-PET and MRI after surgery

Measured

Volume of tumour on FET-PET and MRI

TBRmax and TBRmean Median follow-up was 15.4 months (3-35) Prognostic value of TBR was evaluated


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Conclusions

Tumour volume in FET-PET after surgery ofGBM

has strong prognostic impact for patients FET-PET appears helpful in determining the

residual tumour volume after surgery and mayserve as a valuable tool for optimal planning of

radiation treatment


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Documents

Glioblastoma Tien 2011