Management of Low Grade Gliomas

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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_at_neurosurgery.ufl.edu

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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
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• 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

• 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

Different detectors, equipment, management,
outcomes!
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US Primary Adult Brain Tumors

• 1,800/yr diagnosed with LGG
• LGGs 20 of CNS gliomas

Central Brain Tumor Registry of the US, 2005 -2006
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Diagnosis
Radiographical Clinical Pathologic
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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
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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.

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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

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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/jou
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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

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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/
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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

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Subtype Examples, Contd

•  Juvenile pilocytic astrocytomas (JPAs)
• Typically, occur lt 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/S1
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Treatment

• Indications
• Measurements
• Multidisciplinary Care Teams
• Tumor Supportive Treatments

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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!

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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

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Neuro-Oncology Multidisciplinary Care Team

• Palliative symptom care specialists
• Nurses
• Social workers
• Pathologists
• Radiologists
• Researchers
• Research Office Staff
• Trainees

• Therapists
• Trial Coordinators
• Psychologists, Pharmacists
• Psychiatrists
• Genetic counselors
• Nutritionists
• Neuro-Oncologists

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Our Multidisciplinary Team at the
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Specialty Teams
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Neurosurgery

• leaders in applying modern microsurgical and
  image guided techniques
• latest microsurgical, computer assisted, and
  radiosurgical techniques
• patented UF Radiosurgery System, has treated gt
  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
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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 therapies.
• robust tissue repositories and clinical databases

Erin M. Dunbar, MD Amy A. Smith, MD
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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 research
  institutions devoted to the nervous system and
  its disorders

Dennis Steindler, PhD Brent Reynolds, PhD

• Additional faculty
• Eric Laywell, PhD
• Wolfgang Streit, PhD
• David Borchelt, PhD
• And many others

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Neuro-Pathology

• specializes in intra-operative diagnoses, tissue
  preservation and specialized diagnostic testing
• diagnoses gt500 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
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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 facility
• Part of the UF Radiosurgery Team
• UF and consortium trials

Robert J. Amdur, MD William Mendenhall, MD
Additional Faculty Nancy Mendenhall, MD Robert
Malayapa, MD Sameer Keole, MD
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Neuro-Radiology

• Provides complete adult and pediatric
  neuroimaging services
• Provides imaging-guided biopsies
• Provides consultative services
• Research Collaborations

Ronald G. Quisling, MD

• Additional Faculty
• Jeffery Bennett, MD
• Fabio Rodriguez, MD
• Anthony A. Mancuso, MD

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Many Other Specialists

• Neuro-Rehabilitation
• Neurology
• Neuro-Intensive care
• Neuro-Anesthesia
• Psychology and Psychiatry

• Pain management
• Psychology Psychiatry
• Genetic Screening
• Palliative Services
• Hyperbaric Oxygen Therapy

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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

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Clinical ResearchBasic Translational Research
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Basic Translational Research

• Numerous novel UF investigator, consortium,
  industry, government sponsored trials
  experiments
• Please visit www.neurosurgery.ufl.edu

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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

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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

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Maximal Safe Resection

• Diagnosis molecular characterization
• Debulk tumor and mass-effect
• Alter symptoms
• /- add local therapy

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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

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Tumor Resection Pre-Operative
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Tumor Resection Intra-Operative
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Radiation (RT)

• Ionizing radiation
• DNA damage
• Preferential damage to rapidly dividing cells

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Fractionated, External Beam
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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 gt6 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

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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.

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Chemotherapy

• Must cross the blood brain barrier
• Often augments effects of radiation
• Various actions

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Examples of Chemotherapy
Cytotoxic
Cytostatic chemo-therapy
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Cytotoxic Chemotherapy

• Typically, causes DNA lesions
• ExampleTemozolomide (Temodar)
• Minimizes the repair of damaged DNA
• Via silencing the DNA repair protein MGMT

Malcolm, JM, et al, Am J Cancer, 02
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Cytostatic ChemotherapyExamples 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
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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 gt PCV gt clinical
  trials
• Controversies include
• measurement of response, optimal timing,
  long-term toxicities, alteration of LGG natural
  history, etc.

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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 (lt40yo, 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-toxicitie
  s
• Examples of retrospective or small prospective
  trials of chemotherapy for 25-45
• Usually temozolomide and partial responses

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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.!

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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.

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Our Future
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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!
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Information, Support, Trials

• Information
• 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!

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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.

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Well see you at
Fall 2009
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The End

• Thank you

352-273-9000 www.neurosurgery.ufl.edu edunbar_at_neur
osurgery.ufl.edu