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Radiation for Glioblastoma


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Understanding and treating malignant glioma

Published in: Health & Medicine

Radiation for Glioblastoma

  1. 1. Malignant GliomaRobert Miller
  2. 2. Brain primary: a normalbrain cell (glial cell)becomes malignant and iscalled a gliomaBrain metastases: cancerthat started elsewhere in thebody (e.g. lung or breast)and spread to the brain
  3. 3. Malignant GliomasGlioblastomas 60 to 70%Anaplastic Astrocytomas for 10 to 15%Anaplastic Oligodendrogliomas 10%Less common tumors such as anaplastic ependymomasand anaplastic gangliogliomas account for the rest.
  4. 4. The incidence of these tumors has increased slightly overthe past two decades, especially in the elderly, primarily asa result of improved diagnostic imaging.Malignant gliomas are 40% more common in men than inwomen and twice as common in whites as in blacks.The median age of patients at the time of diagnosis is 64years in the case of glioblastomas and 45 years in the caseof anaplastic gliomas.Who Gets Brain Cancer?
  5. 5. MenCancerMenBrainWomanCancerWomanBrainDiagnosed44% 0.67% 37% 0.55%Dying 24% 0.49% 20% 0.39%Probability of getting or dyingof a brain cancer
  6. 6. Symptoms of Brain Tumor Headaches Seizures Visual changes, Changes in personality, mood, mental capacity, andconcentration Gastrointestinal symptoms such as nausea, loss ofappetite, and vomiting.Seizures are a presenting symptom in approximately 20% ofpatientsAmong all patients with brain tumors, 70% with primary tumorsand 40% with metastatic brain tumors develop seizures at sometime during the clinical course
  7. 7. Brain Swelling – brain tumors often cause swelling oredema which creates pressure on the brain, with headachesand nausea, steroids like Decadron (dexamethasone) willdecrease this pressure
  8. 8. Symptom Grade III Grade IVSymptoms by Grade
  9. 9. Types of Primary BrainTumorsBenign: meningioma, pituitary, pinealMalignant: those that start with glialcells (glue) astrocyte oroligodendrocyteGrade: low grade (I and II)astrocytoma and high grade (III or IV,more mutated and more rapidgrowing)
  10. 10. Type PercentMeningioma 33.4%Glioblastoma 17.6%Pituitary 12.2%Nerve Sheath 8.7%Astrocytoma 7.4%Oligodendroglioma 2.1%Medulloblastoma 1.0%Types of Brain Tumors
  11. 11. Histologic Criteria of the World HealthOrganization for the Classification ofGliomas.Fibrillary astrocytomaAnaplastic astrocytomaGlioblastoma multiforme
  12. 12. The Grade of the Glioma is critical inmaking estimates of prognosis
  13. 13. Malignant GliomaHistology Percent SurvivalAnaplasticastrocytoma7% 50% (1p/19q)27%Glioblastoma 54% < 5%
  14. 14. Some cells in the normal brain undergogenetic alterations, which leads to apopulation of tumor–initiating cells (TICs),which can then further accumulate geneticand epigenetic changes and become braincancer–propagating cells (BCPC).
  15. 15. The latter cells are responsible for the formation ofmultiple subtypes of glioblastoma.
  16. 16. AgeIncidence by Age and Type ofBrain Tumor
  17. 17. Survival
  18. 18. Brain Imaging
  19. 19. GlioblastomaCertain braintumors .e.g.glioma have adistinctappearance onMRI scan . Withirregular bordersand necroticcenter
  20. 20. Glioblastomacells in green,spread diffuselythrough the brainand are hard totarget accuratelyfor radiosurgeryand hard to cutout
  21. 21. Glioblastoma spreads diffuselythrough the brain
  22. 22. Glioblastoma are rapid growing cancers
  23. 23. Glioblastoma are rapid growing cancers andoften outgrow their blood supply so the center ofthe tumor is literally dead cells or necrotic
  24. 24. Malignant Glioma can appear as acomplex cystic structure
  25. 25. occasionally a glioblastoma may appear asmultiple separate tumors and look metastaticdisease (called a multicentric glioblastoma)
  26. 26. Brain Metastasis as seen on an MRI Scan, thesharp margins may make this a better case forhighly targeted radiation
  27. 27. Brain Metastasis has sharp bordersand Is easier to surgically resect ortarget with radiosurgery
  28. 28.
  29. 29. The current standard of care is to treat glioblastoma patientswith surgical resection, followed by temozolomide (Temodar,TMZ) concomitant with external beam radiation (XRT), and thensubsequently with additional TMZ cycles.Despite this treatment, patients have a median survival of 14.6months and an overall survival of 27% at 2 years, that drops tounder 10% at 5 years.Analysis of treatment failure patterns has revealed that up to80% of recurrences occurred within 2 cm of the tumormargins. This was the basis for inclusion of a margin from theresidual tumor and resection cavity, typically of 2–3 cm, whenradiation treatment portals were designed. More recentdata have demonstrated that now the majority of treatmentfailures are within the irradiated field
  30. 30. Brain SurgeryRegardless of tumor type, the bestoutcome if the surgeon removes as muchtumor as possible, keeps the surgicalmorbidity (complications) low and anensures an accurate diagnosis
  31. 31. (C) An intraoperative microscopic view (white light) of the tumor resectioncavity is shown. (D) An intraoperative microscopic view of tumorfluorescence (indicated by arrows) using “blue light” is shown.Fluorescence-Guided Resectionof a Glioblastoma
  32. 32. High Grade Glioma
  33. 33. High Grade Glioma
  34. 34. High Grade Glioma
  35. 35. High Grade Glioma
  36. 36. High Grade Glioma
  37. 37. High Grade Glioma
  38. 38. High Grade Glioma
  39. 39. 100% – normal, no complaints, no signs of disease90% – capable of normal activity, few symptoms or signs of disease80% – normal activity with some difficulty, some symptoms or signs70% – caring for self, not capable of normal activity or work60% – requiring some help, can take care of most personalrequirements50% – requires help often, requires frequent medical care40% – disabled, requires special care and help30% – severely disabled, hospital admission indicated but no riskof death20% – very ill, urgently requiring admission, requires supportivemeasures or treatment10% – moribund, rapidly progressive fatal disease processes0% – death.Karnofsky scoring
  40. 40. Glioblastoma
  41. 41. Glioblastoma
  42. 42. Glioblastoma
  43. 43. Benefit to PostOp Radiation forGlioblastomaTrial by Walker (J NeuroSurg 1978:49:333)S only 14 weeksS + BCNU 18.5 weeksS + XRT 35 weeksS + XRT/BCNU 34.5 weeksTrial (Kristiansen Cancer 1981:47:649)S only 5.2 monthsS + XRT 10.8 months
  44. 44. Radiation Dose
  45. 45. Brain RadiationIn general radiation should start as soon aspossible after surgery and combined withTemodar.Radiation is daily, Monday through Friday for6 weeks
  46. 46. Side Effects of Whole BrainRadiation1. Hair loss (usually takes two or three weeks to happen)2. Mild skin itching or irritation3. Short term more fatigue or slightly more confusion ormemory problems4. Mild headache or nausea is uncommon but may requiremedication (Decadron)5. Occasionally hearing problems (fluid behind the eardrums)
  47. 47. Long Term Effects of Radiation on the BrainThis patient had no symptoms, but radiation may effectmemory
  48. 48. Risk of white matter changes (leukoencephalopathy) 1year after whole brain radiation for brain metsU Pitt Study E Monaco (AANS 2012, Medscape Med News 2012-05-01)WB+SRS SRS1 year 97.3% 3.2%So by one year 97% has some changes andby 2 years 70% had grade 3 changes on theMRI (but no symptoms)
  49. 49. Radiosurgery for Brain Tumors
  50. 50. Radiosurgery forGBMA total of 203 patients with supratentorial GBM were randomlyassigned either to postoperative SRS followed by EBRT (60 Gy)plus BCNU (80 mg/m(2) Days 1-3 every 8 weeks for six cycles) orto EBRT with BCNU alone.RESULTS:At a median follow-up time of 61 months, the median survival in theradiosurgery group was 13.5 months as compared with 13.6 monthsfor the standard treatment groupInt J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):853-60.Radiation Therapy Oncology Group 93-05
  51. 51. Treatment for Recurrent GliomaThe median survival for patients undergoing surgeryfor recurrent GBM ranges from 3 to 8 months andranges from 13 to 20 months for patients with AA.In a series of 114 consecutive patients with recurrentmalignant gliomas treated with SRS, the medianprogression-free survival for patients with grade 3 andgrade 4 tumors was 8.6 and 4.6 months, respectively.Radiation-induced necrosis was observed in 24percent of cases.Series with fractionated stereotactic radiotherapy(FSRT) Median survival after reirradiation was 8months for patients with GBM, 16 months for patientswith grade 3 tumors
  52. 52. Brain MRI before surgery (a) shows a periventricular contrast-enhancing mass, PostoperativeMRI (b) shows gross total resection. The patient underwent XRT and concomitant TMZ. Twomonths after adjuvant therapy, follow-up MRI (c) shows a small recurrent nodule outside thetumor cavity. This was targeted with SRS. Isodose lines around the lesion (d) treated with 20 Gyat the 85% isodose line (e). Follow-up MRI (f) shows radiographic control up to 19 months laterRadiosurgery for Recurrent GBM
  53. 53. Comparison of stereotactic radiosurgery andbrachytherapy in the treatment of recurrentglioblastoma multiforme.Shrieve DC, Loeffler JS. Neurosurgery 1995 Feb;36(2):275-82;Brain Tumor Center, Brigham and Womens Hospital, Boston,Massachusetts, USA.Twenty-one patients (24%) treated with SRS were alive, with a medianfollow-up of 17.5 months.Median actuarial survival, measured from the time of treatment forrecurrence, for all patients treated with SRS was 10.2 months, withsurvivals of 12 and 24 months being 45 and 19%, respectively.
  54. 54. 1. There is evidence of no benefit when givenas part of the original therapy as a boost toconventional radiation2. Not enough evidence to determine benefitwhen given for recurrent cases3. Not enough evidence to determine a benefitwhen given as primary therapydata up to 2004
  55. 55. 0 5 10 15 20 25 30Time (months)Overall survival after SRS (72% at 6 mos, 38% at 12 mos)Combs. Cancer 2005;104:2168)Median survival 10 monthsThirty-two patients with recurrent glioblastoma multiforme(GBM) were treated for 36 lesions with SRS from 1993 to2001
  56. 56. Efficacy of stereotactic radiosurgery as a salvagetreatment for recurrent malignant gliomasCompared with this historic control group, SRS significantly prolongedsurvival as a salvage treatment in patients with recurrent glioblastomas (23months vs 12 months)Doo-Sik Kong, Cancer 2008;112:2046
  57. 57. Hypofractionated Stereotactic RadiationTherapy: An Effective Therapy for RecurrentHigh-Grade GliomasJCO June 20, 2010 vol. 28 no. 18 3048-3053The median time from diagnosis to H-SRT was11 months for grade 3 patients, and 8 months forgrade 4 patients.
  58. 58. Studies of stereotactic radiosurgery asadjunct treatment for recurrent high-gradegliomas
  59. 59. Studies of stereotactic radiosurgery +molecular targeting agent as adjuncttreatment for recurrent high-gradegliomas
  60. 60. Gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumabcombined with chemotherapy in 11 patients with recurrent glioblastomamultiforme who experienced tumor progression despite aggressive initialmulti-modality treatment.median margin dose of GKSR was 16 Gy (range 13-18 Gy). FollowingGKSR, bevacizumab was administrated with irinotecan in nine patients andwith temozolomide in one patient. One patient was treated withbevacizumab monotherapy.The treatment outcomes were compared to 44 case-matched controls whounderwent GKSR without additional bevacizumab.The median overall survival (OS) from GKSR was 18 months and 1-year OSrate was 73%. the patients who received bevacizumab had significantlyprolonged and (18 months vs. 12 months)Park KJ. J Neurooncol. 2012 Apr;107(2):323-33
  61. 61. Clinical Outcomes of Gamma Knife Radiosurgery in the SalvageTreatment of Patients with Recurrent High-Grade Glioma.World Neurosurg. 2013 Feb 9. pii: S1878-8750Gamma knife radiosurgery has become increasingly popular as a salvagetreatment modality for patients diagnosed with recurrent high-grade glioma.The purpose of this article is to review the efficacy of gamma kniferadiosurgery for patients who suffer from this malignancy.Retrospective, prospective, and randomized clinical studies publishedbetween the years 2000 and 2012 analyzing gamma knife radiosurgery forpatients with high-grade glioma were reviewed.evidence suggests that gamma knife radiosurgery provides patients with ahigh local tumor control rate and a median survival after tumor recurrenceranging from 13 to 26 months. Gamma knife radiosurgery followed bychemotherapy for recurrent high-grade glioma may provide select patientswith increased levels of survival.
  62. 62. Complications ofRadiosurgery Short term side effects are uncommon(2%) with worsening symptoms or newseizures About one third mild swelling(headaches, nausea) Radionecrosis in 5% to 10% in primarycases but may be 24% or higher inretreat cases
  63. 63. Sometimes the MRIwill look worse afterradiosurgery due toradionecrosis of thecancer this mayslowly go away butmay require repeatsurgery
  64. 64. Chemotherapy
  65. 65. ChemotherapyEORTC Trial: Randomized trial of 573 GBM(<70y)Temodar + XRT XRTmedian survival 14.6 mos 12.1 mossurv/2y 26.5% 10.4%surv/5y 10% 2%Lancet Oncology 2009;10:459
  66. 66. Lancet Oncology 2009;10:459EORTC Trial GBM
  67. 67. ChemotherapyMGMT hypermethylation willrespond better to Temodar (survival9.7 months versus 6.8 months)
  68. 68. Molecular Predictors of Progression-Free and Overall Survival inPatients With Newly Diagnosed Glioblastoma: A ProspectiveTranslational Study of the German Glioma NetworkJCO December 1,2009 vol. 27no.34 5743-5750
  69. 69. Molecularchangesfound inGBM areallpotentialtargets fornewtargetedtherapies
  70. 70. Abnormalcell cyclepathwaysin GBM alltargets fornewmoderntargetedtherapy
  71. 71. Chemotherapy/TargetedTherapy
  72. 72. Multiplefactors thateffect survivaland most ofthis data isolder dataand may notapply to anewlydiagnosedpatients
  73. 73. RTOG Data showed survival was related to age,type of malignant glioma and performance scoreand mental status
  74. 74. Group Median survival Survival at 2 yearsI 58 – 68 months 64 – 76%II 37 – 57 months 67 – 68%III 17 – 22 months 35 – 45%IV 11 – 13 months 8 – 15%V 8 – 9 months 3 – 6%VI 4 - 5 months 3 – 4 %Data from Curran JNCI 1993;85:704 and Kleinberg IJROBP 1997;38:31Survival by RTOG Group
  75. 75. Group 1: Age ≤40, frontal tumor.Group 2: Age ≤40, other tumor sites.Group 3: Age >40 and <65; KPS >70 and gross or subtotalresection.Group 4: Age ≥65 or age <40; or KPS ≤70; or biopsy only.GBM Survival
  76. 76. Group Criteria SurvivalBest No steroids, KPS > 90, notGBM20.2 monthsMedium Everything not in worst 7.4 monthsWorst On steroids, age > 50, GBM 4.7 monthsSurvival with RecurrentMalignant Glioma
  77. 77.
  78. 78. Malignant GliomaRobert Miller