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)

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 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

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

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

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

• 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

The Enemy

Peter Bent Brigham Hospital