Successes and Frustrations in the Management of Malignant Gliomas
Edward R. Laws and colleaguesBrigham & Women’s Hospital
Gliomas of the Brain
• 70% of Primary Brain Tumors
• Mean Age at Diagnosis is 55
• 60-70% are Malignant (Glioblastoma)
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 andResection Cohorts
Age - Biopsy Group Older
Pathology - Resection Group More GBM
KPS - Biopsy Group More KPS <70
Location - All Multifocal (27), More Bilat in Biopsy Group
Size - Larger in Resection Group
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
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
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
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
• 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
• Polyclonal heterogeneity
• Tumor cell resistance
• Tumor cell metabolism
• Tumor cell invasion and migration
• Tumor oxygenation
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
Unique Characteristics of Tumor
• Growth kinetics• Vascular supply• Glycloytic metabolism• Tumor cell invasion
• 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
• 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
• 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
• 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
• 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