Management of Low Grade

Gliomas
Erin M. Dunbar, MD
Medical Neuro-Oncology
Co-Director, Preston A. Wells, Jr., Center for Brain Tumor Therapy
at the University of Florida
352-273-9000
www.neurosurgery.ufl.edu
edunbar@neurosurgery.ufl.edu
 Low Grade Gliomas (LGGs)
Primary CNS tumors composed of one or more
type of neuroglial cells
ependymal cells, astrocytes, oligodendrocytes, etc
Divided into subtypes
based upon their histopathologic appearance
based on known differences in behavior
Develop anywhere, but most often in the
cerebral hemispheres, optic pathways,
brainstem
Vary in malignant behavior, but without
anaplasia (= HGGs)

Selections of this presentation generally reference the free, online

patient resource: Up-to-date patient information:
www.uptodate.com/patients/index.html
High-grade Gliomas (HGGs)
More consistent growth speed
and symptoms
Typically, trimodality therapy
at diagnosis
Typically, continued treatment
(until intolerance/toxicity)
Typically, more consistent and
inferior outcome
Different detectors, equipment, management, & outcomes!
Low Grade Gliomas
More variable growth speed
and symptoms
Typically, uni or bimodality
therapy at diagnosis
Typically, intermittent
treatment (clinical and/or
radiographic
progression/recurrence)
Typically, less consistent and
inferior outcome
 US Primary Adult Brain Tumors
~1,800/yr diagnosed with LGG
LGGs = ~ 20% of CNS gliomas
Gliomas
27%
Germ Cell

Schwanoma
46%
Sellar
Tumors
3% Other

9%
Lymphoma

Meningioma
7%
7% 1% Central Brain Tumor Registry of the US, 2005 -2006
Diagnosis
Radiographical
Clinical
Pathologic
 Radiographic Diagnosis
MRI (and CT)
Standard for imaging
Typically in cerebral
hemispheres
Typically, little mass-effect
~80% non-contrast
enhancing at presentation
Exception: JPAs
Calcifications, sometimes
Usually odendrogliomas
Functional imaging
Emerging role for imaging
Positron-emission
tomography (PET)
Typically cold (glucose
hypo-metabolism)
Thallium-201 SPECT
Etc.

imaging.birjournals.org
 Clinical Diagnosis
Symptoms from:
location of the tumor
Weakness, ataxia,
seizures, etc.
seizures can be as high
as ~80%
result of increased
intracranial pressure
headache, change in
mental status, etc.

http://content.revolutionhealth.com/contentimages/images-image_popup-ww990304.jpg
 Prognosis
Improving!
In general, longer survival than HGGs,
regardless of treatment
Highly variable, likely impacted by:
Histologic subtype
Age
General health
Performance status (functionality, activity)
Anatomical location
Unique profile of tumor
Preferences & approach to treatment
 Pathologic Diagnosis
Degree of Malignancy
Absence of anaplasia (= defines HGGs)
Example of grading system
Cell Type of Origin
Pure vs mixed
Example of subtypes.
Molecular/Genetic
19/19q co-deletion by FISH
=Oligodendroglioma lineage
chromosomal abnormality, short arm of
chromosome 1 (1p) & the long arm of
chromosome 19 (19q)
Prognostic for improved outcome,
regardless of treatment

http://www.neuropathologyweb.org/chapter7/images7/7-gemisto.jpg;
http://www.nature.com/modpathol/journal/v18/n9/thumbs/3800415f1th.jpg
 WHO Grading System (evolves)
Low-grade
WHO Grade I i.e., Juvenile Pilocytic Astrocytoma

WHO Grade II i.e., Diffuse Astrocytoma

High-grade
WHO Grade III i.e., Anaplastic Astrocytoma

WHO Grade IV i.e., Glioblastoma Multiforme

http://www.suck.uk.com/photos/FireBucket1.jpg
 Examples of LGG Subtypes
Diffuse astrocytomas
Most common LGG,
peak ~ mid-30s
Survival highly
variable, average ~ 7
yrs
Typically, slow
clinical/radiographic
progression initially
Usually speeds &
eventually
progresses to ~
HGGs

http://www.nature.com/ncponc/journal/v4/n6/images/ncponc0820-f1.jpg
 Subtype Examples, contd
Oligodendrogliomas
Less common, peak ~ late 30s
Survival highly variable, but ~ 10
yrs
most common in cerebral
hemispheres
Typically, seizures
Often, calcifications
imaging or under the microscope
Typically, better outcome than
other LGGs, regardless of therapy
especially with 1p/1q co-deletions
Typically, more responsive to
chemotherapy
especially with 1p/1q co-deletions

http://www.neuropathologyweb.org/chapter7/images7/7-15l.jpg
 Subtype Examples, Contd
Juvenile pilocytic astrocytomas (JPAs)
Typically, occur < 25 years
Typically, in cerebellar hemispheres & around 3rd ventricle
Typically cystic, well-demarcated, and contrast-enhancing
Typically, substantially better outcome than other LGGs
Can be cured by resection
Gangliogliomas
Typically, in temporal lobe
Typically, seizures
History and outcome ~ JPAs
Ependymomas
Typically, occur in young
Typically, around 4th ventricle
More variable outcome
impacted by age, extent of resection, histology
Other rare LGGs
pleomorphic xanthoastrocytomas, subependymomas,
desmoplastic gangliogliomas
Typically, long history
Can be cured by resection

http://www.neuropathologyweb.org/chapter7/images7/7-16b.jpg
http://www.pathconsultddx.com/images/S1559867506702327/gr1-sml.jpg
 Treatment
Indications
Measurements
Multidisciplinary Care Teams
Tumor & Supportive Treatments
 Indications for Treatment
Radiographic
Clinical
Seizures, especially if progressive and/or difficult to
manage medically
Increased intracranial pressure (mass-effect)
Etc.
Timing
i.e., at diagnosis or at progression
Highly individualized
Preferences and approach
Patient, providers
Controversial
Evolving!
 Measurements of Treatment
Response
For both Radiographic and Clinical:
Difficult
i.e., LGGs often non-enhancing and ill-defined
i.e., prolonged natural history
Controversial
i.e., clinical improvement without radiographic
improvement
Impacts: Diagnosis, Natural History,
Response to treatment
Evolving
The most reliable end point remains survival
 Neuro-Oncology
Multidisciplinary Care Team
Therapists Palliative & symptom
Trial Coordinators care specialists
Psychologists, Nurses
Pharmacists Social workers
Psychiatrists Pathologists
Genetic counselors Radiologists
Nutritionists Researchers
Neuro-Oncologists Research Office Staff
Trainees
Our Multidisciplinary Team at the
Specialty Teams
 Neurosurgery
leaders in applying modern
microsurgical and image guided
techniques
latest microsurgical, computer
assisted, and radiosurgical
techniques
patented UF Radiosurgery System,
has treated > 2800 patients
Novel translational & clinical
research
William A. Friedman, MD David W. Pincus, MD, PhD
Additional Faculty:
Albert J. Rhoton, Jr., MD
J. Richard Lister, MD, MBA
Kelly D. Foote, MD
Brian L. Hoh, MD
Stephen B. Lewis, MD
Steven N. Roper, MD
R. Patrick Jacob, MD
Gregory A. Murad, MD
Jay Mocco, MD
Jobyna Whiting, MD
R. Rick Bhasin, MD
 Medical Neuro-Oncology
provides a full complement of
comprehensive adult and
pediatric services
novel UF clinical research
participation in consortium and
industry-sponsored research
experimental & palliative Erin M. Dunbar, MD Amy A. Smith, MD

therapies.
robust tissue repositories and
clinical databases
 Neuroscience
Novel individual and
collaborative investigations
A full spectrum of research,
from fundamental discovery
to clinical application
Evelyn F. and William L.
McKnight Brain Institute: one
of the worlds largest Dennis Steindler, PhD Brent Reynolds, PhD

research institutions devoted

to the nervous system and its
disorders
Additional faculty:
Eric Laywell, PhD
Wolfgang Streit, PhD
David Borchelt, PhD
And many others
 Neuro-Pathology
specializes in intra-operative
diagnoses, tissue preservation
and specialized diagnostic
testing
diagnoses >500 brain tumors a
year and provides national
consultative referral services
Provide diagnoses for the
Florida Center for Brain Tumor
Research, a statewide brain
tumor bank and associated
database Jing Qui, MD, PhD Anthony T. Yachnis, MD, MS

Additional faculty:
Tom A. Eskin, MD
 Radiation-Oncology
provides state-of-the-art
external beam radiation and
brachytherapy using a team
approach
The University of Florida,
Jacksonville, houses the
proton therapy treatment Robert J. Amdur, MD William Mendenhall, MD
facility
Additional Faculty:
Part of the UF Radiosurgery
Team Nancy Mendenhall, MD

UF and consortium trials Robert Malayapa, MD

Sameer Keole, MD
 Neuro-Radiology
Provides complete adult
and pediatric
neuroimaging services
Provides imaging-guided
biopsies Ronald G. Quisling, MD

Provides consultative Additional Faculty:

services Jeffery Bennett, MD
Fabio Rodriguez, MD
Research Collaborations Anthony A. Mancuso, MD
 Many Other Specialists
Neuro- Pain management
Rehabilitation Psychology &
Neurology Psychiatry
Neuro-Intensive Genetic Screening
care Palliative Services
Neuro-Anesthesia Hyperbaric Oxygen
Psychology and Therapy
Psychiatry
 Multidisciplinary Care
Patent navigator for patients & referrals
Coordinated clinic visits
Coordinated hospital care
Tumor boards
Education and support services
Education & Support Group
Education room in Clinic and on Wards
Transportation between care
 Clinical Research
Basic & Translational Research
 Basic & Translational
Research

Numerous novel UF investigator,

consortium, industry, government
sponsored trials & experiments

Please visit
www.neurosurgery.ufl.edu
 Tumor & Supportive
Treatment
Goals:
Prolong overall survival
Prolong progression-free survival
Promote quality of life (QOL)
Improve, maintain, slow the decline
Promote neurologic function
Improve, maintain, slow the decline
Minimize treatment-related effects
Prevent, minimize, delay the onset, improve
Tumor Treatment Options
Optimal strategy remains unknown
timing, order, and combinations
Maximal safe resection
Pre-Operative:
Imaging that identifies areas of function
Peri-Operative:
MRI-guided surgery
Patient wake and being tested
Radiation
External beam
Fractionated
Chemotherapy
Various timing, types, combos
Maximal Safe Resection

Diagnosis & molecular characterization

Debulk tumor and mass-effect
Alter symptoms
+/- add local therapy
 Surgery Contd
Timing
Immediately, if a large mass or extensive symptoms
Delayed, if small mass or minimal symptoms
Careful clinical & radiographic surveillance begins
Subsequent resection, if concern for progressive mass or
symptoms
especially if medically refractory or concern for HGG
Extent of resection
Maximal safe resection when feasible, especially if
symptomatic or presumed diagnosis is unclear
because of infiltrative nature, gross total resection is often
not possible
Biopsy when resection not feasible, if minimal symptoms, if
presumed to be LGG
No prospective randomized trials
numerous (inherently biased) retrospective reviews
report improved outcome with earlier and
more maximal resection
Tumor Resection: Pre-Operative
Tumor Resection: Intra-Operative
 Radiation (RT)

Ionizing radiation
DNA damage
Preferential damage to rapidly dividing
cells
Fractionated, External Beam
 Radiation (RT), Contd
Timing
Immediate, if significant mass or symptoms
especially if only biopsy or presence of high-risk features
= astrocytic, significant disease-related neurological
symptoms recurrent or progression, age 40, size >6
cm, tumor crossing midline, high cell activity
Delayed, if minimal mass or symptoms
including after resection
Subsequent RT, rarely performed
i.e., unless recurrence/progression is in new location
Extent
Typically conforming to within 1-2.5 cm of abnormality
Typically ~54 Gy, external beam, fractionated, in six weeks
 RT, contd
Controversy remains over the relative effects
of recurrence/progression vs. the treatment
Randomized, prospective trials:
Timing of RT
EORTC 22845 randomized patients (after biopsy or sub-total resection)
to receive either immediate RT or no therapy until progression.
At a median follow-up of almost eight years, immediate
postoperative RT significantly prolonged the progression-free
survival (median 5.4 versus 3.7 years, without postoperative
RT), but did not affect overall survival (7.4 versus 7.2 years).
Better seizure control was observed among patients receiving
postoperative RT.
Dose and schedule of RT
EORTC 22844 & a North American Multi-center trial both failed to show
a survival benefit from escalation of the dose of RT.
Other fractionation techniques (hyper-fractionated and fractionated
stereotactic radiotherapy) have not shown benefit.
 Chemotherapy

Must cross the blood brain barrier

Often augments effects of radiation
Various actions
Examples of Chemotherapy
Cytotoxic

Cytostatic
chemo-
therapy
 Cytotoxic Chemotherapy

Typically, causes DNA

lesions
Example:Temozolomide
(Temodar)
Minimizes the repair of
damaged DNA
Via silencing the DNA
repair protein MGMT

Malcolm, JM, et al, Am J Cancer, 02

 Cytostatic Chemotherapy
Examples include Biologic, Small molecules, Targeted agents

Typically, more targeted action

(treatment) to the target cell;
Less targeted action (damage) to
bystander cells.
Example: Vascular-endothelial
growth factor receptor (VEGF-R)
inhibition (Bevacizumab (Avastin))
Alters edema & imaging-features
Normalizes the vasculature
Hopefully facilitates chemotherapy
into the tumor & inhibits tumor

Vregenbergh, J, JCO, 2007; Clinical

Ce Res, Feb 2007
 Chemotherapy, contd
Timing
Typically, reserved for recurrence
However, despite a lack of strong evidence, increasing trends
for:
Increasing now with oligodendrogliomas, especially with
1p/19q co-deletion
Increasingly used because of emergence of presumably
more tolerable or safe chemosreally?
Often used for symptoms, especially medically refractory
seizures
Regimens
Numerous, not often compared prospectively
Typically, temozolomide-based > PCV > clinical trials
Controversies include:
measurement of response, optimal timing, long-term
toxicities, alteration of LGG natural history, etc.
 Chemotherapy, contd
Clinical Trials
Difficulty to interpret trials that include diverse histologies
One example, RTOG 9802, prospectively randomized trial failed
to show improved outcome with routine post-operative chemo
patients with favorable prognosis (<40yo, gross total
resection) randomized to observation
patients with unfavorable prognosis (those age 40 years or
whose surgery was a subtotal resection or biopsy only)
randomized to to postoperative RT (54 Gy in 30 fractions)
plus six cycles of PCV chemotherapy or the same dose of RT
without chemotherapy
Progression free survival was slightly improved, but at the
expense of moderate treatment-toxicities
Examples of retrospective or small prospective trials of
chemotherapy for ~ 25-45%
Usually temozolomide and partial responses
 Treatment at
Recurrence/Progression
Controversy over true tumor progression vs.
pseudo-progression (aka: treatment effect,
radiation-necrosis)
Single or multimodality combinations of re-
resection, radiation, and chemotherapy are
all used
Highly individualized
Goals & preferences, age, overall health, etc.!
 Supportive Treatment
-Extraordinarily Important!
-Cerebral Edema
-Seizures
-Iatrogenic side-effects (from treatment)
-Neurologic deficits of all types
-Myelo-suppression, infection
-Fatigue
-Neuro-cognitive
-organ-toxicity
-radiation-necrosis
-etc.
Our Future
 Future Improvements Needed!
Areas of remaining controversy include:
Important of extent of resection
Timing of RT +/- chemo
Upfront or at recurrence/progression
An aggressive treatment approach including immediate surgical
intervention versus a delayed intervention in patients with limited
disease and symptoms
Relative contribution of the toxicities of the tumor recurrence
vs. the treatment
Role of chemotherapy-only approaches
Are newer chemos really safer and more effective?
Importance of treating different LGG subtypes differently
Molecular/genetic profile, etc.
QOL, neurological performance status
Patient & caregiver, resource utilization

Many being addressed in trials now!

 Information, Support, &
Information Trials
www.uptodate.com/patients
www.plwc.org
www.cancer.gov
Support
www.fbta.org
www.braintumor.org
www.abta.org
Trials
www.neurosurgery.ufl.edu
www.cancer.gov
www.clinicaltrials.gov
Brain Tumor Center websites

MANY MORE!
 Future
Your ideas & partnership is needed
Unanswered questions and unmet needs
Collaboration in care, research, education, &
advocacy
I warmly welcome you to contact
me regarding:
Multidisciplinary care
Support group & educational events
Website & Hope Heals Run
FCBTR tissue donation
Etc.
Well see you at

Fall 2009
 The End
Thank you

352-273-9000
www.neurosurgery.ufl.edu
edunbar@neurosurgery.ufl.edu