Glioblastoma Multiforme.Dr NG NeuroEdu

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Glioblastoma Multiforme.Dr NG NeuroEdu

  1. 1. Current Management of GBM Nishantha Gunasekera Neurosurgery, Waikato 1
  2. 2. “ better a living problem than a dead certainty ” 2
  3. 3. Epidemiology WHO estimates- 100 different types ofbrain tumours 22 500 new cases –malignant primaries(US ’07) Annual incidence of malignant gliomas5/100000 GBM: 60-70% Anaplastic astros: 10-15% Anaplastic oligos/oligoastros: 10% 3
  4. 4. THE most common primary brain tumour Biologically aggressive Mean age at presentation 56-64 yr Median survival 12-15 months Presents unique treatment challengesWe Can do something positive for most 4
  5. 5.  40% commoner in men Twice as more in whites than non whites The only established risk factor is ionisingradiation Head injury, n-nitroso compounds in food,electromagnetic fields???? IgE ? protective 5% have family history NF 1,2 ; Li- Fraumeni syn (p53); Turcot’s GLIOGENE – an international consortium  (to study familial gliomas) 5
  6. 6. Challenges The variably disrupted blood-brain barriercomplicating drug delivery Tumour capillary leakage – oedema, ICP Limited response to therapy Neurotoxicity of treatment Molecular pathology is complex – butimportant recent advances have been made 6
  7. 7.  Localisation of tumours in the brain Intrinsic resistance of tumour to conventional therapy Limited capacity of the brain to repair itself The spread of malignant cells into brainparenchyma 7
  8. 8. Predictors of outcome Patient age (18 month survival)  <40y - 50%  40-60 - 20%  >60 - 10% Histological features  median survival 10 months for “classic GBMs ’’ Performance status (18 month survival)  KPS>70 34%  KPS<60 13% 8
  9. 9. Pathophysiology p53 mutation- sets the stage for malignanttransformation Allelic loss of ch17p- malignant progression Many growth factors/receptors are over expressed  PDGF (platelet)  FGF (fibroblast)  VEGF (vascular endothelial)  EGFR (epidermal) Progression to WHO Gr II is associated with  Increased cellularity  Mitotic activity 9
  10. 10.  GBM is characterised by  Dense cellularity  High proliferation indices (Ki67-protein marker of prolif.)  Vascular endothelial proliferation  Focal necrosis Source of mitogenesis is deregulation ofthe p16-cdk4-cyclin D1-pRb pathway Ch 10p loss is a frequent finding (60-95%) 1p19q deletion may indicate betterprognosis- (oligo. component) Various subsets of GBM exist dependingon the molecular genetics 10
  11. 11. 11
  12. 12. Histology 12
  13. 13. 13
  14. 14. Spread Tracking through white matter  Corpus callosum  Cerebral peduncles – midbrain  Internal capsule – encroach basal ganglion t. Into centrum semiovale  Uncinate fasciculus – simultaneous frontal and temporal  Interthalamic adhesions – bilateral thalamic gliomas CSF pathways  10-25% frequency of meningeal and ventricular seeding V. rarely systemic 14
  15. 15. Clinical features Due to raised ICP Progressive focal deficits  Stroke in evolution!! Headache  With or without raised ICP  Worse in the morning – hypoventilation, co2  relieved by vomiting - ? Hyperventilation  77% similar to tension h/a; 9% like a migraine  Only 8% had “classic tumour headache’’ Siezures (AOE) Mental status changes 16
  16. 16. Investigations CT contrast / non contrast MRI / fMRI/ MR spectroscopy Stealth imaging (CT/MRI) Tractography Intra-operative brain mapping (for awake surgery) 17
  17. 17. c+ct 18
  18. 18. mri 19
  19. 19. fmri 20
  20. 20. mri spectroscopyn acytyl aspartate peak = infectioncholine peak = tumour 21
  21. 21. tractography 22
  22. 22. intrapoerative mapping 23
  23. 23. Treatment Treatment has evolved to include 1. Maximum safe extent of resection 2. Fractionated radiotherapy to tumour bed 3. Alkylating chemotherapy (nitrosoureas: BCNU)  based on trials by BTSG (brain tumour study group) and RTOG (radiation therapy oncology group) 24
  24. 24. 25
  25. 25. Treatment issues Siezures (levetiracetam does not induce P450) Peritumoural oedema (VEGFR inhibitors) Venous thromboembolism (20-30%, IVC filters,anticoagulation) Cognitive dysfunction Steroid associated probs. (Cushings, P. jiroveci etc. etc.) Abulia (lack of will or initiative) - ? methylphenidate 26
  26. 26.  Value of total or near total resection still isdebated but... Data from BTSG suggests large volumeresection has a better outcome... Value of adjuvant chemotherapy has beenevaluated by meta-analyses (Fine et al,Stewart et al) Modest improvement in 1-2 y survival rates (5-6% and 4-5% respectively) 27
  27. 27.  Glioma Outcome Project data ‘05 (560 newlydiagnosed GBM- 58 community and university centresinvolved) all patients underwent surgery 87% received radiotherapy 88% received anticonvulsants 54 % received chemo 29% used alternative meds15% enrolled in clinical trials 28
  28. 28.  These studies clearly demonstrated a benefit for chemotherapy (that is, TMZ) in the initialtreatment of patients with GBM Improvement in median (14.6 compared with 12months) and 2-year survival (27 comparedwith 10%) in patients receiving or not receivingTMZ.Consequently, this treatment regimen (TMZ givenconcurrently with radiotherapy, followed by six monthlycycles of TMZ) has become the new standard of care forpatients with newly diagnosed GBM. 29
  29. 29. Surgery Cytoreductive Extent of tumour removal and the volume of residual tumour on post op imaging have a significant effect on time to tumourprogression and median survival Mass effect reduction CANNOT be cured with surgery.. can it? Prolong quality of survival In the elderly (>65y), the benefit by surgery ismodest (median survival 17w after biopsy, 30 w after surgery : +XRT) 30
  30. 30.  Partial resection of GBMs carries asignificant risk of post op haemorrhage,oedema with risk of herniation Benefit of subtotal resection is deemeddubious Surgical excision should be only considered when the goal of gross total resection isfeasible 31
  31. 31.  The following are usually not surgicalcandidates  Extensive dominant lobe GBM  Lesions with bilateral involvement (butterfly)  Deep lesions (brain stem, capsule)  The very elderly  Patients with poor Karnofsky scores  In general the neurologic condition on steroids is as good as its going to get- surgery rarely improves this 32
  32. 32. Surgical Toys Neuronavigation  Offline  Realtime (brain suite- intraopeative MRI) Fluorescence guided Intraoperative mapping 33
  33. 33. Brain Suite 34
  34. 34. Stereotactic Biopsy May underestimate by 25% Located in deep areas Small T. with minimal mass effect Patients with poor medical conditions Equivocal clinical diagnosis ( lymphoma!) 35
  35. 35.  Stereotactic  Frame based  Frameless- stealth Free hand 36
  36. 36. Reoperation for recurrence Less than 10% recur away from the original site Reoperation extends survival by anadditional 36 weeks Duration of high quality survival was 10weeks Predictors of good quality of survival afterreoperation include Age, time from 1st to 2nd surgery, Karnofsky 37
  37. 37.  Morbidity is higher (5-18%) Infection rate is > X3 Wound dehiscence more Neurological deficits more Surgical techniques differ 38
  38. 38. Radiation Usual dose of XRT is 50-60 Gy – wholebrain radiation has not been shown toincrease the median survival compared tofocal XRT but the risks of side effects isgreater Brachytherapy has not shown no significant benefit as an adjunct to EBRT 39
  39. 39. Chemotherapy All current agents have no more than 30-40% response rate Carmustine and cisplatinum have been the primary agents Temazolamide  An oral alkylating agent  Initial FDA approval for relapse or progression of anaplastic astros. while on a nitrosourea containing regimen  Now also used for newly diagnosed GBM and AA and progressive low grade gliomas 40
  40. 40. Chemotherapy GLIADEL wafers  Carmustine 7.7mg in 200mg prolifeprosan 20 hydrophobic polymer carrier (wafer)  Following T. removal upto 8 wafers are applied to the resection bed (US$12500 for 8)  Drug is released over 2-3 wks  Exposes the tumour to 113 times the conc. of BCNU achieved by systemic admin.  Approved by FDA for recurrent GBM 41
  41. 41. DrugResistance 42
  42. 42. NewTherapies 43
  43. 43. What next?  can we prevent?  can we screen?  can we immunize? 45

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