1. Challenges and Frustrations in the Management of Malignant Glioma Edward R Laws and Colleagues Brigham & Women’s Hospital

2. Successes and Frustrations in the Management of Malignant Gliomas Edward R. Laws and colleagues Brigham & Women’s Hospital

3. MD Patient Types of Outcomes Survival Treatment Morbid events Function Satisfaction Expectations

4. GO Project: 58 Clinical Sites

5. Primary Outcomes Studied Practice patterns Quality of life Satisfaction Survival

6. Gliomas of the Brain 70% of Primary Brain Tumors Mean Age at Diagnosis is 55 60-70% are Malignant (Glioblastoma)

7. The Glioma Outcomes Project

8. Rationale for a Glioma Outcomes Study Most Retrospective Studies Show Survival Advantage for Resection when Compared to Biopsy + Adjunctive Therapy Very Few Adequate Prospective Studies Exist Contemporary Data From An Observational Study Can Provide An Estimate of Survival Differences

9. Enrollment Criteria Primary brain tumors Grade III or IV Initial operation 18 years or over Informed patient consent

10. Follow-up Intervals Postop (enrollment) 1-3 weeks initial follow-up 3-month intervals Endpoint - 24 months or death

11. Types of Primary Brain Tumors Studied Glioblastoma multiforme Anaplastic oligodendroglioma Mixed anaplastic oligo/astrocytoma Anaplastic gliomas (Grade III or IV)

12. Cumulative Patient Enrollment (n=788)

13. Patient Data 788Malignant Glioma Patients Accrued 1997 - 2000 639 Followed At Least 15 Months or Until Death 446 With Complete Data

14. Differences Between Biopsy and Resection Cohorts Age-Biopsy Group Older Pathology-Resection Group More GBM KPS-Biopsy Group More KPS <70 Location-All Multifocal (27), More Bilatin Biopsy Group Size-Larger in Resection Group

15. Arguments for Radical Resection

16. CYTOREDUCTION Decrease the Tumor Burden

17. Pathologic Diagnosis More Secure Sampling Error Reduced

18. Statistics Multistep Theory of Malignant Progression Number of Cells at Risk

19. Intracranial Pressure is Relieved Neurologic Deficits are Reversed Seizures are Eliminated

21. The Late Effects of Radiation Therapy Cognitive, Emotional Demyelination, Necrosis

22. Arguments Against Radical Resection

23. Inherent Invasiveness of Most Gliomas

24. Infiltrative Tumors Cannot be Totally Resected

25. Multifocal and Multilobular Gliomas

26. Potential for Surgical Complications and New Neurological Deficits

27. Pathology - 446 Patients GBMF (73%) Grade III Gliomas(27%)

28. Survival by Tumor Grade

29. Survival by Pathology GBMFMean Survival = 43 Weeks Grade III GliomaMean Survival = 66 Weeks

30. Survival for Biopsy vs. Resection

31. Favorable Prognostic Factors Age 20 - 40 Karnofsky Rating  70 Resection

32. Unfavorable Prognostic Factors Age  60 Multifocal Tumor Karnofsky Rating < 70 Biopsy Only

33. Age Group 20 - 40 41 - 60 > 60 Mean Survival (# of Patients) 61 Weeks (31) 53 Weeks (111) 37 Weeks (127) Survival Related to Age - GBMF

34. Age Group 20 - 40 41 - 60 > 60 Mean Survival (# of Patients) 84 Weeks (35) 74 Weeks (230) 39 Weeks (18) Survival Related to Age - Grade III Glioma

35. Survival for Biopsy vs. Resection

36. Survival “Tail” at 96 Weeks GBMF = 10% Grade III Glioma = 70%

37. Adjunctive Therapies by Pathology Therapy Radiotherapy/Radiosurgery Chemotherapy GBMF 76% 50% Grade III Glioma 71% 55%

38. Data Set 1 All Patients Under 65 Yrs. of Age; N=342 BiopsyCrani Number Path = GBM KPS > 70 Midline + Bilat 68 55% 72% 15% 274 66% 81% 3%

39. Survival for Biopsy vs. Resection

40. Data Set 2 All Patients Under 65; Multifocal and Bilateral Excluded; N=296 BiopsyResectio n Number of Patients Path = GBM KPS > 70 Tumor > 4 cm 52 51% 71% 47% 244 66% 82% 56%

41. Patient Survival-Age<65 With Unifocal, Unilateral Tumors

43. Data Set 3 All Patients Under 65; Multifocal and Bilateral Excluded; KPS < 70 Excluded; N=228 Biopsy Crani Number of Patients Path = GBM Size > 4 cm 36 49% 46% 192 61% 54%

44. Patient Survival-Age 70 With Unifocal, Unilateral Tumors

45. Survival is Improved with Radical Resection

46. Methods for Improving Radical Resection Functional MRI Electrophysiological Monitoring Image Guided Surgery and Intraoperative Ultrasound Imaging Intraoperative MRI Metabolic Imaging Awake Surgery

47. Survival for Patients with Malignant Gliomas Little Changed in 40 years – Except Perhaps for Quality of Life

48. The Enemy

49. Malignant Glioma Survival Statistics have not changed in 40 years

50. Resection vs Biopsy Mean Survival by Type of Surgery Resection - 356 Patients - 53 Weeks Biopsy - 96 Patients - 34 Weeks

51. Problems in Glioma Treatment Invasion and multifocality – local therapy will never be curative Impact of radiotherapy and chemotherapy on quality of life Cerebral edema and other reactions to tumor cell death Analysis of resected tumor may be misleading

52. What do we Believe? They start monoclonal, but rapidly develop polyclonal instability A sequence of molecular genetic events results in malignancy Activation of oncogenes and deletion of suppressor genes play a role in pathogenesis Some are malignant de novo; some progress from more benign lesions

54. More Concepts Anaerobic metabolism prevails DNA repair mechanisms fail Drug and radiation resistance develop Necrosis and antiapoptotic phenomena occur Incidence increases with increasing age Relative immunosuppression is often present

56. More Concepts Some type of dedifferentiation occurs, leading to migration and invasion of tumor cells (proteases, NCAMS) Angiogenesis develops to sustain tumor mass (abnormal vessels, endothelial proliferation, loss of BBB) 20% are multifocal Metastasis outside the CNS is extremely uncommon

58. Problems in Brain Tumor Therapy Polyclonal heterogeneity Tumor cell resistance Tumor cell metabolism Tumor cell invasion and migration Tumor oxygenation

59. Problems in Brain Tumor Therapy Characteristics shared with normal brain Tumor-brain interface phenomena Blood- brain barrier phenomena Delivery of toxic agents Tumor Stem Cells may Produce Tumors

60. Unique Characteristics of Tumor Growth kinetics Vascular supply Glycloytic metabolism Tumor cell invasion Oxygenation pH Blood-brain barrier Peritumoral invasion

62. Targets for Tumor Cell Destruction Cell surface/nuclear receptors Cell membrane/nuclear/mitochondrial membranes Mitochondria-energy production Cytoskeleton Protein synthesis – cytoplasm/nucleus Signal transduction processes

63. Targets for Tumor Cell Destruction RNA – transcription, synthesis, polymerases DNA – purine/pyrimidine incorporation, strand breaks, hydrogen bonding, methylation, repair mechanisms Phospholipids – membrane structures Cytokines – intracellular and cell-to-cell signalling

64. Targets for Tumor Cell Destruction Mitochondrial DNA Oncogenes and Tumor Suppressor Genes Polyamines – growth and development regulation Replication point mutations, amplifications

66. Mechanisms of Tumor Cell Destruction Free radicals – oxygen, peroxide, hydroxyl Direct ionizing reactions Alkylation/carbamylation of bases Inhibition of enzyme action Alterations of nucleic acid structure & function Angiogenesis inhibition Immunotherapy

67. Malignant Gliomas – What is Effective Surgical Resection Conventional Fractionated Radiotherapy Nitrosoureas (marginally) Temazolamide – in some (MGMT methylation)

68. Malignant Gliomas – What is Ineffective (So Far) Hyperfractionation, Hypofractionation, Radiation Sensitizers, Oxygenation Brachytherapy, Radiosurgery, BNCT Photoradiation, Hyperthermia Gene Therapy Monoclonal Antibodies, Immunotherapy Angiogenesis Inhibitors, Protease Inhibitors, Signal Transduction Blockers, Cytokines Hormone, Steroid, Vitamin Based Therapy

70. Other Ineffective Therapies In vitro chemotherapy testing Differentiation therapy Stem Cells Chemotherapy ( iv,intrarterial,intrathecal, BBBD, Polymer, Convection, BM rescue)

72. Why Have We Failed Wrong treatment strategies – focal therapies for a diffuse disease Wrong tissue studied – resected tissue may not represent what is left behind Poor or misleading models Inadequate understanding of developmental neurobiology

74. Proposal for Management Maximally resect Analyze tumor margin to guide therapy Inhibit invasion/migration Use radiotherapy judiciously Consider immunotherapy and vaccination strategies

75. For Incomplete Resection Maximize quality of life and cognitive function Judicious radiotherapy – Focal + Antiangiogenesis agents Antimetabolites

76. The Enemy

77. Peter Bent Brigham Hospital