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

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do

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Tumour

Brain

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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

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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