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Successes and Frustrations in the
Management of Malignant Gliomas
Edward R. Laws and colleagues
Brigham & Women’s Hospital
Gliomas of the Brain
• 70% of Primary Brain Tumors
• Mean Age at Diagnosis is 55
• 60-70% are Malignant (Glioblastoma)
The Glioma Outcomes Project
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
Types of Primary Brain Tumors
Studied
• Glioblastoma
multiforme
• Anaplastic
oligodendroglioma
• Mixed anaplastic
oligo/astrocytoma
• Anaplastic gliomas
(Grade III or IV)
Patient Data
• 788
Malignant Glioma Patients
Accrued 1997 - 2000
• 639
Followed At Least 15 Months or
Until Death
• 446
With Complete Data
Differences Between Biopsy and
Resection Cohorts
Age
Pathology KPS
-
Location Size
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Biopsy Group Older
Resection Group More
GBM
Biopsy Group More KPS
<70
All Multifocal (27), More
Bilat in Biopsy Group
Larger in Resection Group
Arguments for Radical Resection
CYTOREDUCTION
Decrease the Tumor Burden
Pathologic Diagnosis More
Secure
• Sampling Error
Reduced
Statistics
• Multistep Theory of
Malignant Progression
• Number of Cells at
Risk
Intracranial Pressure is Relieved
Neurologic Deficits are Reversed
Seizures are Eliminated
The Late Effects of Radiation
Therapy
Cognitive, Emotional
Demyelination, Necrosis
Arguments Against Radical
Resection
Inherent Invasiveness of Most
Gliomas
Infiltrative Tumors Cannot be
Totally Resected
Multifocal and Multilobular
Gliomas
Potential for Surgical
Complications and New
Neurological Deficits
Pathology - 446 Patients
GBMF
(73%)
Grade III Gliomas (27%)
Survival by Tumor Grade
Survival for Biopsy vs. Resection
Favorable Prognostic Factors
Age 20 - 40
Karnofsky Rating  70
Resection
Unfavorable Prognostic Factors
Age  60
Multifocal Tumor
Karnofsky Rating < 70
Biopsy Only
Survival Related to Age - GBMF
Age Group
Mean Survival (# of Patients)
20 - 40
61 Weeks (31)
41 - 60
53 Weeks (111)
> 60
37 Weeks (127)
Survival Related to Age - Grade III
Glioma
Age Group
Mean Survival (# of
Patients)
20 - 40
84 Weeks (35)
41 - 60
74 Weeks (230)
> 60
39 Weeks (18)
Patient Survival-Age<65 With
Unifocal, Unilateral Tumors
Patient Survival-Age<65 With
Unifocal, Unilateral Tumors
Patient Survival-Age<65,
KPS>70 With Unifocal,
Unilateral Tumors
Survival is Improved with
Radical Resection
Methods for Improving Radical
Resection
• Functional MRI
• Electrophysiological Monitoring
• Image Guided Surgery and Intraoperative
Ultrasound Imaging
• Intraoperative MRI
• Metabolic Imaging
• Awake Surgery
Survival for Patients with
Malignant Gliomas
Little Changed in 40 years –
Except Perhaps for Quality of Life
The Enemy
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
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
More Concepts
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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
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
Problems in Brain Tumor
Therapy
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Polyclonal heterogeneity
Tumor cell resistance
Tumor cell metabolism
Tumor cell invasion and migration
Tumor oxygenation
Problems in Brain Tumor
Therapy
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Characteristics shared with normal brain
Tumor-brain interface phenomena
Blood- brain barrier phenomena
Delivery of toxic agents
Tumor Stem Cells may Produce Tumors
Unique Characteristics of Tumor
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Growth kinetics
Vascular supply
Glycloytic metabolism
Tumor cell invasion
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Oxygenation
pH
Blood-brain barrier
Peritumoral invasion
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
Mechanisms of Tumor Cell
Destruction
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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
Malignant Gliomas –
What is Effective
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Surgical Resection
Conventional Fractionated Radiotherapy
Nitrosoureas (marginally)
Temazolamide – in some (MGMT
methylation)
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
Other Ineffective Therapies
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In vitro chemotherapy testing
Differentiation therapy
Stem Cells
Chemotherapy ( iv,intrarterial,intrathecal,
BBBD, Polymer, Convection, BM rescue)
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
Proposal for Management
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Maximally resect
Analyze tumor margin to guide therapy
Inhibit invasion/migration
Use radiotherapy judiciously
Consider immunotherapy and vaccination
strategies
For Incomplete Resection
• Maximize quality of life and cognitive
function
• Judicious radiotherapy – Focal +
• Antiangiogenesis agents
• Antimetabolites
The Enemy
Peter Bent Brigham Hospital