1. Oncology management of CNS tumours Neil Burnet University of Cambridge Department of Oncology & Oncology Centre, Addenbrookes Hospital ECRIC CNS study day 7 th April 2009

2. Treatment modalities for cancer What data do oncologists want? Examples of uses of Registry data Introduction

4. Cancer treatment modalities

5. Modalities (Surgery) Radiotherapy Chemotherapy Consider efficacy Consider costs

6. Oncology management

8. 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

9. CT – the technology advance Late 1970s 1980s 2003

10. Glioblastoma imaging T2 T1 T1 + Gd contrast MR (magnetic resonance) imaging

11. Radiotherapy Immobilise the patient Relate today's patient position to tumour imaging

12. Radiotherapy High precision positioning Relocatable stereotactic frame

13. Radiotherapy

14. Radiotherapy imaging CT MRI

15. MRI CT GBM planning Using CT +MR together

16. Radiotherapy imaging Pre-op CT Post-op planning CT

17. Target volume delineation

18. 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) 21 st century technology

19. Treatment volumes compared Square plan ConformalUltra- conformal IMRT

20. Old square planning

21. Some shielding with lead blocks

22. Treatment volumes compared Square plan ConformalUltra- conformal IMRT

23. Conformal RT plan

24. IMRT plan (TomoTherapy) Ca nasopharynx 68 Gy to primary (34#) 60 Gy to nodes (34#) Cord dose < 45 Gy No field junctions No electrons

25. IMRT plan Skull base meningioma Shaping of dose around optic nerves and chiasm Tumour ~ 60 Gy Optic chiasm 50 Gy

27. Radiotherapy dose Biological effect depends on Total dose Number of fractions (Dose per fraction) Overall treatment time Complex relationship

28. 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

29. RT dose and fractions For a given dose, and overall time, biological effect depends on number of # Actually depends on dose/#

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

31. Chemotherapy Most chemo for CNS tumours is oral Temozolomide Invented in UK Revolutionised treatment of GBM

32. RT + TMZ for GBM P<0.001 EORTC Randomised trial results

33. Cancer cure and cost

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

35. The Cancer Reform Strategy Prof. Mike Richards 2007

36. Effectiveness and cost % cures% of cancer Ratio care cost Radiotherapy 40% 5% 8.0 Chemotherapy 11% 18% 0.6 Surgery 49% 22% 2.2

37. What data do oncologists really want?

38. 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?

39. Tumour types in oncology clinic Note ~20% with benign tumours

40. CNS tumour types - 1 Glial tumours Astrocytoma (inc Pilocytic & Juvenile Pilocytic) Oligodendroglioma Oligo-astrocytoma Glioblastoma (GBM) Ependymoma (+ subependymoma) Meningioma Pituitary adenoma + Craniopharyngioma

41. CNS tumour types - 2 Vestibular schwannoma (aka acoustic neuroma) Medulloblastoma Germinoma + teratoma Lymphoma Neurocytoma + Ganglioglioma Pineoblastoma Primitive neuro-ectodermal tumour (PNET) (Chordoma + chondrosarcoma) (Metastases)

42. 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

43. Grade affects prognosis High grade glioma Grade III Grade IV = GBM - Surgery + RT only - Radical treatment - Addenbrookes data

44. Grade affects prognosis Histology is not the only tumour feature which affects outcome

45. Radiology adds to pathology grade Need to include information from imaging Radiotherapy & Oncology 2007; 85:371-378

46. What data do oncologists really want? Prognostic factors Age Performance status ? Size Extent of surgical resection (hard to evaluate) Treatment intent Radical Palliative

47. 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?

48. Radiotherapy details Area treated Total dose Number of fractions Overall treatment time Dates Time (delay) to start RT Overall time (duration) of RT

49. Chemotherapy details Drug(s) Dose Number of cycles given Dates

51. Measuring disease burden - AYLL GBM outcome Modelling chemotherapy use Examples of Registry data use

52. 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

53. 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

54. 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

55. 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

56. Average Years of Life Lost

57. 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

58. 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/Dear colleagueletters/DH_080975

59. 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

60. Burnet et al. Br J Cancer 2005; 92(2): 241-5 Average Years of Life Lost per affected patient versus %NCRI spending

61. GBM outcome 2

62. GBM – traditionally terrible outloook Addition of temozolomide (TMZ) chemotherapy has transformed the outlook Can we reproduce trial results? The scream – Edvard Munck

63. TMZ + RT for GBM P<0.001 EORTC Randomised trial results

64. TMZ + RT for GBM Addenbr RT alone

65. TMZ + RT for GBM Addenbr RT + TMZ Addenbr RT alone

66. TMZ + RT for GBM P<0.001 Addenbr RT+TMZ

67. GBM outcome Our results match the international trial Endorsement of our treatment pathway Good news for patients ! Patient photo

68. Modelling chemotherapy use 3

69. 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?

70. TMZ treatment schema 0 6 10 14 18 22 26 30 34 RT TMZ 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

71. 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

72. EORTC trial Model - RT + concurrent TMZ RT + concurrent TMZ near perfect fit

73. 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

74. 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 OSullivan, Chemotherapy Pharmacist, Addenbrookes Hospital

75. Modelling chemotherapy use UK Population 60 m GBM cases (33 x 60)1,980 p.a. GBM patients treated radically50% Number requiring TMZ990 p.a.

76. Modelling chemotherapy use UK Population 60 m GBM cases (33 x 60)1,980 p.a. GBM patients treated radically50% Number requiring TMZ990 p.a. Cost TMZ £11 m p.a. Saving by using only concurrent TMZ £ 7 m p.a.

77. Improving survivorship AW on the beach AS at Christmas Patient photo Photo of patient and family

78. 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