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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 day 7 th April 2009. Introduction . Treatment modalities for cancer What data do oncologists want? Examples of uses of Registry data.

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oncology management of cns tumours neil burnet

Oncology management of CNS tumoursNeil Burnet

University of Cambridge Department of Oncology & Oncology Centre, Addenbrooke’s Hospital

ECRIC CNS study day

7th April 2009

introduction
Introduction
  • Treatment modalities for cancer
  • What data do oncologists want?
  • Examples of uses of Registry data
cancer treatment modalities5
Cancer treatment modalities
  • Modalities
    • (Surgery)
    • Radiotherapy
    • Chemotherapy
    • Consider efficacy
    • Consider costs
radiotherapy
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
CT – the technology advance

Late 1970s 1980s 2003

glioblastoma imaging
Glioblastoma imaging
  • T2
  • T1
  • T1 + Gd contrast

MR (magnetic resonance) imaging

radiotherapy11
Radiotherapy
  • Immobilise the patient
  • Relate today\'s patient position to tumour imaging
radiotherapy12
Radiotherapy
  • High precision positioning
  • Relocatable stereotactic frame
slide15

GBM planning

  • Using CT +MR together

MRI CT

radiotherapy imaging16
Radiotherapy imaging
  • Post-op planning CT
  • Pre-op CT
radiotherapy18
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
slide19

Treatment volumes compared

Conformal

Ultra-conformal IMRT

‘Square’ plan

slide22

Treatment volumes compared

Conformal

Ultra-conformal IMRT

‘Square’ plan

imrt plan tomotherapy
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
IMRT plan
  • Skull base meningioma
  • Shaping of dose around optic nerves and chiasm
  • Tumour ~60 Gy
  • Optic chiasm 50 Gy
radiotherapy dose
Radiotherapy dose
  • Biological effect depends on
    • Total dose
    • Number of fractions

(Dose per fraction)

    • Overall treatment time

Complex relationship

radiotherapy dose28
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
RT dose and fractions
  • For a given dose, and overall time, biological effect depends on number of #
  • Actually depends on dose/#
chemotherapy
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
chemotherapy31
Chemotherapy
  • Most chemo for CNS tumours is oral
  • Temozolomide
    • Invented in UK
    • Revolutionised treatment of GBM
rt tmz for gbm
RT + TMZ for GBM

EORTC

Randomised trial results

P<0.001

cancer cures by modality
Cancer cures by modality
  • References
  • SBU. The Swedish council on technology assessment in health care: Radiotherapy for Cancer. 1996
  • Cancer Services Collaborative 2002
slide35

The Cancer Reform Strategy

Prof. Mike Richards 2007

effectiveness and cost
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 want38
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
tumour types in oncology clinic
Tumour types in oncology clinic
  • Note ~20% with benign tumours
cns tumour types 1
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
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
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
Grade affects prognosis
  • High grade glioma
  • Grade III
  • Grade IV = GBM

- Surgery + RT only

- Radical treatment

- Addenbrooke’s data

grade affects prognosis44
Grade affects prognosis
  • Histology is not the only tumour feature which affects outcome
slide45

Radiotherapy & Oncology 2007; 85:371-378

  • Radiology adds to pathology grade
  • Need to include information from imaging
what data do oncologists really want46
What data do oncologists really want?
  • Prognostic factors
    • Age
    • Performance status
    • ? Size
    • Extent of surgical resection (hard to evaluate)
  • Treatment intent
    • Radical
    • Palliative
what data do oncologists really want47
What data do oncologists really want?
  • 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
radiotherapy details
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
Chemotherapy details
  • Drug(s)
  • Dose
  • Number of cycles given
  • Dates
examples of registry data use
Examples of Registry data use
  • Measuring disease burden - AYLL
  • GBM outcome
  • Modelling chemotherapy use
measuring disease burden
Measuring disease burden

1

  • 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
measuring disease burden53

Diagnosis

Death

Life expectancy at diagnosis

Years of Life Lost

Measuring disease burden
  • Method
    • Detail deaths from specific tumour type
    • Compare to standardised matched population
    • Sum the difference
measuring disease burden54
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
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
measuring disease burden57
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 lost58
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 burden59
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
slide60

Average Years of Life Lost per affected patient versus %NCRI spending

Burnet et al. Br J Cancer 2005; 92(2): 241-5

gbm outcome62
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
TMZ + RT for GBM

EORTC

Randomised trial results

P<0.001

tmz rt for gbm64
TMZ + RT for GBM

Addenbr RT alone

tmz rt for gbm65
TMZ + RT for GBM

Addenbr RT + TMZ

Addenbr RT alone

tmz rt for gbm66
TMZ + RT for GBM

Addenbr RT+TMZ

P<0.001

gbm outcome67
GBM outcome
  • Our results match the international trial
  • Endorsement of our treatment pathway
  • Good news for patients !

Patient photo

modelling chemotherapy use69
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
TMZ treatment schema
  • Chemo-RT programme with temozolomide (TMZ)

RT

TMZ

  • Component 1
    • Concurrent with RT
    • Daily for 42 days
  • Component 2
    • Adjuvant
    • 5 days every 28, x 6 cycles

Week

0 6 10 14 18 22 26 30 34

modelling chemotherapy use71
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
slide72

EORTC trial

Model - RT + concurrent TMZ

RT + concurrent TMZ

near perfect fit

modelling chemotherapy use73
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 use74
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 use75
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 use76
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
Improving survivorship

Patient photo

  • AW on the beach

Photo of patient and family

  • AS at Christmas
acknowledgements
Acknowledgements
  • Colleagues
    • Sarah Jefferies
    • Raj Jena
    • Fiona Harris
    • Phil Jones
  • Peter Treasure
  • Norman Kirkby
  • Lara Barazzuol
  • EORTC
  • 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
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