oncology management of cns tumours neil burnet
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Oncology management
of CNS tumours
Neil Burnet
University of Cambridge Department of Oncology & Oncology Centre, Addenbrooke’s Hospital
ECRIC CNS study day7th April 2009
• Treatment modalities for cancer
• What data do oncologists want?
• Examples of uses of Registry data
Introduction
Cancer treatment modalities
Cancer treatment modalities
• Modalities
• (Surgery)
• Radiotherapy
• Chemotherapy
• Consider efficacy
• Consider costs
Oncology management
Radiotherapy
• Radiotherapy is an anatomical treatment
• Treats a specific area
• Localising the tumour target is crucial
• Imaging is key
• Better localisation – better outcome
• Localising normal structures allows avoidance
CT – the technology advance
Late 1970s 1980s 2003
Glioblastoma imaging
• T2 • T1 • T1 + Gd contrast
MR (magnetic resonance) imaging
Radiotherapy
• Immobilise the patient
• Relate today's patient position to tumour imaging
Radiotherapy
• High precision positioning
• Relocatable stereotactic frame
Radiotherapy
Radiotherapy imaging
CT MRI
MRI CT
• GBM planning
• Using CT +MR together
Radiotherapy imaging
• Pre-op CT • Post-op planning CT
Target volume delineation
Radiotherapy
• Planning and delivery technology now very different
• Old ‘square’ planning• Was conventional in 1960s – 1990s
• Conformal (dose conforms to shape of target in 3D)
• ‘Ultra-conformal’ (includes concave shape)• known as IMRT (intensity modulated radiotherapy)
• 21st century technology
Treatment volumes compared
‘Square’ plan Conformal Ultra-conformal
IMRT
• Old ‘square’ planning
• Some shielding with ‘lead’ blocks
Treatment volumes compared
‘Square’ plan Conformal Ultra-conformal
IMRT
Conformal RT plan
IMRT plan (TomoTherapy)
• Ca nasopharynx
• 68 Gy to primary (34#)
• 60 Gy to nodes (34#)
• Cord dose < 45 Gy
• No field junctions
• No electrons
IMRT plan
• Skull base meningioma
• Shaping of dose around optic nerves and chiasm
• Tumour ~ 60 Gy
• Optic chiasm 50 Gy
Radiotherapy dose
• Biological effect depends on
• Total dose
• Number of fractions
(Dose per fraction)
• Overall treatment time
Complex relationship
Radiotherapy dose
• Single fraction
• Very destructive
• Known as radiosurgery
• Must physically avoid normal tissue
• Multiple fractions
• Spare normal tissue
• Enhances therapeutic radio
• Allows treatment including normal tissue
RT dose and fractions
• For a given dose, and overall time, biological effect depends on number of #
• Actually depends on dose/#
Biologically Effective Dose for 60 Gyfor variable fraction number
0
200
400
600
800
1000
1200
1 5 10 15 20 25 30
Fractions
Bio
log
ical
do
se
Tumour
Brain
0
200
400
600
800
1000
1200
1 5 10 15 20 25 30
Chemotherapy
• Use in accordance with NICE Guidelines
• At first presentation, with (surgery &) RT• Temozolomide
• Also at relapse• PCV
• Monitor• Blood count, nausea, liver function (+ other s/e)• Progression
Chemotherapy
• Most chemo for CNS tumours is oral
• Temozolomide
• Invented in UK
• Revolutionised treatment of GBM
RT + TMZ for GBM
P<0.001
EORTCRandomised trial results
Cancer cure and cost
Cancer cures by modality
References
• SBU. The Swedish council on technology assessment in health care: Radiotherapy for Cancer. 1996
• Cancer Services Collaborative 2002
Funding World Class Cancer Care (Chapter 10)
Total expenditure: Around £4.35bn pa in England.
Expenditure per head of population = £80 (compared with £121 in France and £143 in Germany)
0 200 400 600 800 1000 1200 1400
Other [8]
Specialist Palliative Care (excluding voluntary sector) [7]
Radiotherapy [6]
Screening [5]
Outpatients (diagnostics, first and follow-up appointments) [4]
Drugs (cost of medicine, preparation and administration) [3]
Surgery (including day cases and inpatient stays) [2]
Inpatient costs (excluding those related to surgery) [1]
Cost (£ million per annum)
10%
5%
8%
18%
22%
27%
5%
5%
Estimated total NHS spend on cancer care
The Cancer Reform Strategy Prof. Mike Richards 2007
Effectiveness and cost
% cures % of cancer Ratio care cost
• Radiotherapy 40% 5% 8.0
• Chemotherapy 11% 18% 0.6
• Surgery 49% 22% 2.2
What data do oncologists really want?
• What data do oncologists really want or need?
• Types of CNS tumour
• Prognostic factors
• Treatment intent
• Treatment details
• Dates
What data do oncologists really want?
Tumour types in oncology clinic
• Note ~20% with benign tumours
CNS tumour types - 1
• Glial tumours
• Astrocytoma (inc Pilocytic & Juvenile Pilocytic)
• Oligodendroglioma
• Oligo-astrocytoma
• Glioblastoma (GBM)
• Ependymoma (+ subependymoma)
• Meningioma
• Pituitary adenoma + Craniopharyngioma
CNS tumour types - 2
• Vestibular schwannoma (aka acoustic neuroma)
• Medulloblastoma
• Germinoma + teratoma
• Lymphoma
• Neurocytoma + Ganglioglioma
• Pineoblastoma
• Primitive neuro-ectodermal tumour (PNET)
• (Chordoma + chondrosarcoma)
• (Metastases)
CNS tumour types - 3
• Many tumour types
• Prognosis varies enormously• Survival from “days to weeks” to cure• Affected by tumour type• Grade (ie how malignant)
• Essential to know detail• Detail must be collected
Grade affects prognosis
• High grade glioma
• Grade III
• Grade IV = GBM
- Surgery + RT only
- Radical treatment
- Addenbrooke’s data
Grade affects prognosis
• Histology is not the only tumour feature which affects outcome
• Radiology adds to pathology grade
• Need to include information from imaging
Radiotherapy & Oncology 2007; 85:371-378
What data do oncologists really want?
• Prognostic factors
• Age
• Performance status
• ? Size
• Extent of surgical resection (hard to evaluate)
• Treatment intent
• Radical
• Palliative
• Treatment intent
• Might be clear from treatment
• GBM – RT 60 Gy (30#) = radical
30 Gy (6#) = palliative
• Need to know if intent changes
• eg due to progression
What data do oncologists really want?
Radiotherapy details
• Area treated
• Total dose
• Number of fractions
• Overall treatment time
• Dates
• Time (delay) to start RT
• Overall time (duration) of RT
Chemotherapy details
• Drug(s)
• Dose
• Number of cycles given
• Dates
• Measuring disease burden - AYLL
• GBM outcome
• Modelling chemotherapy use
Examples of Registry data use
Measuring disease burden
• Simple mortality figures do not tell the whole story
• Other measures show alternative aspects of mortality:
• Burden on society
• Burden to the individual affected
• With particular thanks to Peter Treasure at ECRIC
1
Measuring disease burden
• Method
• Detail deaths from specific tumour type
• Compare to standardised matched population
• Sum the difference
DeathDiagnosis
Life expectancy at diagnosis
Years of Life Lost
Measuring disease burden
• CNS tumours
• 2% of cancer deaths – simple mortality
• 3% of the years of life lost - YLL
• YLL shows the burden on society
Average Years of Life Lost
• Divide YLL by number of affected patients
• Average Years of Life Lost – AYLL
• AYLL shows the burden to the affected person
• Easily understood measure, including by patients
• CNS tumours account for ~ 20 years of lost life
• This is higher than any other adult tumour type
Average Years of Life Lost
Average Years of Life Lost for 17 cancer sites
0.0
5.0
10.0
15.0
20.0
25.0
Ave
rag
e Y
ears
of
Lif
e L
ost
per
aff
ecte
d in
div
idu
al
Measuring disease burden
• CNS tumours
• 2% of cancer deaths
• 3% of the years of life lost – YLL
• ~ 20 years of lost life per individual - AYLL
Average Years of Life Lost
• In the 2007 Cancer Reform Strategy reference made to the poor overall outcome of brain & CNS tumours in terms of AYLL ¶
• Encouraging that alternative measures of mortality are being acknowledged by the government
¶ UK Government Department of Health (2007) http://www.dh.gov.uk/en/Publicationsandstatistics/Lettersandcirculars/Dearcolleagueletters/DH_080975
Measuring disease burden
• AYLL is an effective measure of disease burden to the affected person
• AYLL has other uses
• Compare disease burden with research spending
• AYLL does not match NCRI research spending
• The mis-match is most extreme for CNS tumours
Burnet et al. Br J Cancer 2005; 92(2): 241-5
Average Years of Life Lost per affected patient versus %NCRI spending
GBM outcome2
GBM outcome
• GBM – traditionally terrible outloook
• Addition of temozolomide (TMZ) chemotherapy has transformed the outlook
• Can we reproduce trial results?
The scream – Edvard Munck
TMZ + RT for GBM
P<0.001
EORTCRandomised trial results
TMZ + RT for GBM
Addenbr RT alone
TMZ + RT for GBM
Addenbr RT + TMZAddenbr RT alone
TMZ + RT for GBM
P<0.001
Addenbr RT+TMZ
GBM outcome
• Our results match the international trial
• Endorsement of our treatment pathway
• Good news for patients !
Patient photo
Modelling chemotherapy use3
Modelling chemotherapy use
• TMZ chemo combined with RT (& surgery) has revolutionised the outcome for patients with GBM
• TMZ is given in 2 parts
• Concurrent daily with RT
• Adjuvant for 6 cycles after RT
• Are both parts of value?
TMZ treatment schema
0 6 10 14 18 22 26 30 34
RTTMZ
• Chemo-RT programme with temozolomide (TMZ)
• Component 2
• Adjuvant
• 5 days every 28, x 6 cycles
• Component 1
• Concurrent with RT
• Daily for 42 days
Week
Modelling chemotherapy use
• Build model of patient survival
• Allow treatment with RT and with chemo
• Fit model to Kaplan Meier survival curves to derive values for tumour growth and response to treatment
• Test
• TMZ + RT = concurrent
• RT followed by TMZ = adjuvant
EORTC trialModel - RT + concurrent TMZ
RT + concurrent TMZnear perfect fit
Modelling chemotherapy use
• RT + concurrent TMZ produces near perfect fit
• Suggests concurrent TMZ is the effective component
• Suggests adjuvant TMZ may not add anything
• Omitting 6 cycles of adjuvant TMZ would:
• Spare toxicity
• Improve QoL (likely) - finish treatment 6/12 earlier
• Save money
Modelling chemotherapy use
• Incidence of GBM• 33 cases per million population per annum
• Cost of TMZ – 1 course• Concurrent £3900• Adjuvant £7100
• With thanks to:• David Greenberg & Peter Treasure,
Eastern Cancer Registration & Information Centre (ECRIC), Cambridge• Brendan O’Sullivan,
Chemotherapy Pharmacist, Addenbrooke’s Hospital
Modelling chemotherapy use
• UK
• Population 60 m
• GBM cases (33 x 60) 1,980 p.a.
• GBM patients treated radically 50%
• Number ‘requiring’ TMZ 990 p.a.
Modelling chemotherapy use
• UK
• Population 60 m
• GBM cases (33 x 60) 1,980 p.a.
• GBM patients treated radically 50%
• Number ‘requiring’ TMZ 990 p.a.
• Cost TMZ £11 m p.a.
• Saving by using only concurrent TMZ £ 7 m p.a.
Improving survivorship
• AW on the beach
• AS at Christmas
Patient photo
Photo of patient and family
Acknowledgements• Colleagues
• Sarah Jefferies• Raj Jena• Fiona Harris• Phil Jones
• National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
• RJ is supported by The Health Foundation, UK
• NFK was supported by an EPSRC discipline-hopping grant
• Peter Treasure
• Norman Kirkby
• Lara Barazzuol
• EORTC
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